The Clinical Assessment, Treatment, and Prevention of Lyme ......IDSA Guidelines • CID 2006:43 (1 November) • 1091 Figure 1. From left to right, an Ixodes scapularis larva, nymph,

IDSA Guidelines • CID 2006:43 (1 November) • 1089

I D S A G U I D E L I N E S

The Clinical Assessment, Treatment, and Preventionof Lyme Disease, Human Granulocytic Anaplasmosis,and Babesiosis: Clinical Practice Guidelines by theInfectious Diseases Society of America

Gary P. Wormser,1 Raymond J. Dattwyler,2 Eugene D. Shapiro,5,6 John J. Halperin,3,4 Allen C. Steere,9

Mark S. Klempner,10 Peter J. Krause,8 Johan S. Bakken,11 Franc Strle,13 Gerold Stanek,14 Linda Bockenstedt,7

Durland Fish,6 J. Stephen Dumler,12 and Robert B. Nadelman1

Divisions of 1Infectious Diseases and 2Allergy, Immunology, and Rheumatology, Department of Medicine, New York Medical College, Valhalla,and 3New York University School of Medicine, New York, New York; 4Atlantic Neuroscience Institute, Summit, New Jersey; Departments of5Pediatrics and 6Epidemiology and Public Health and 7Section of Rheumatology, Department of Medicine, Yale University School of Medicine,New Haven, and 8Department of Pediatrics, University of Connecticut School of Medicine and Connecticut Children’s Medical Center, Hartford;9Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, and 10Boston University School ofMedicine and Boston Medical Center, Boston, Massachusetts; 11Section of Infectious Diseases, St. Luke’s Hospital, Duluth, Minnesota; 12Divisionof Medical Microbiology, Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland; 13Department of InfectiousDiseases, University Medical Center, Ljubljana, Slovenia; and 14Medical University of Vienna, Vienna, Austria

Evidence-based guidelines for the management of patients with Lyme disease, human granulocytic anaplasmosis

(formerly known as human granulocytic ehrlichiosis), and babesiosis were prepared by an expert panel of the

Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines

published in 2000 (Clin Infect Dis 2000; 31[Suppl 1]:1–14). The guidelines are intended for use by health care

providers who care for patients who either have these infections or may be at risk for them. For each of these

Ixodes tickborne infections, information is provided about prevention, epidemiology, clinical manifestations,

diagnosis, and treatment. Tables list the doses and durations of antimicrobial therapy recommended for

treatment and prevention of Lyme disease and provide a partial list of therapies to be avoided. A definition

of post–Lyme disease syndrome is proposed.

EXECUTIVE SUMMARY

Background

Lyme disease is the most common tickborne infection

in both North America and Europe. In the United

Received 21 August 2006; accepted 21 August 2006; electronically published2 October 2006.

These guidelines were developed and issued on behalf of the InfectiousDiseases Society of America.

It is important to realize that guidelines cannot always account for individualvariation among patients. They are not intended to supplant physician judgmentwith respect to particular patients or special clinical situations. The InfectiousDiseases Society of America considers adherence to these guidelines to bevoluntary, with the ultimate determination regarding their application to be madeby the physician in the light of each patient’s individual circumstances.

Reprints or correspondence: Dr. Gary P. Wormser, Rm. 245, Munger Pavilion,New York Medical College, Valhalla, NY 10595 ([email protected]).

Clinical Infectious Diseases 2006; 43:1089–134� 2006 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2006/4309-0001$15.00

States, Lyme disease is caused by Borrelia burgdorferi,

which is transmitted by the bite of the tick species Ixodes

scapularis and Ixodes pacificus. Clinical manifestations

most often involve the skin, joints, nervous system, and

heart. Extracutaneous manifestations are less com-

monly seen than in earlier years. Early cutaneous in-

fection with B. burgdorferi is called erythema migrans,

which is the most common clinical manifestation of

Lyme disease. I. scapularis may also be infected with

and transmit Anaplasma phagocytophilum (previously

referred to as Ehrlichia phagocytophila) and/or Babesia

microti, the primary cause of babesiosis. Thus, a bite

from an I. scapularis tick may lead to the development

of Lyme disease, human granulocytic anaplasmosis

(HGA, formerly known as human granulocytic ehrli-

chiosis), or babesiosis as a single infection or, less fre-

quently, as a coinfection. Clinical findings are sufficient

1090 • CID 2006:43 (1 November) • Wormser et al.

Table 1. Infectious Diseases Society of America–US PublicHealth Service Grading System for ranking recommendationsin clinical guidelines.

Category, grade Definition

Strength of recommendationA Strongly in favorB Moderately in favorC OptionalD Moderately againstE Strongly against

Quality of evidenceI Evidence from �1 properly ran-

domized, controlled trialII Evidence from �1 well-designed

clinical trial, without randomi-zation; from cohort or case-controlled analytic studies(preferably from 11 center);from multiple time seriesstudies; or from dramatic re-sults from uncontrolledexperiments

III Evidence from opinions of re-spected authorities, based onclinical experience, descriptivestudies, or reports of expertcommittees

NOTE. Categories reflect the strength of each recommendation for oragainst use and the quality of the evidence.

for the diagnosis of erythema migrans, but clinical findings alone

are not sufficient for diagnosis of extracutaneous manifestations

of Lyme disease or for diagnosis of HGA or babesiosis. Diagnostic

testing performed in laboratories with excellent quality-control

procedures is required for confirmation of extracutaneous Lyme

disease, HGA, and babesiosis.

Tick Bites and Prophylaxis of Lyme Disease

The best currently available method for preventing infection

with B. burgdorferi and other Ixodes species–transmitted path-

ogens is to avoid exposure to vector ticks. If exposure to I.

scapularis or I. pacificus ticks is unavoidable, measures rec-

ommended to reduce the risk of infection include the use of

both protective clothing and tick repellents, checking the entire

body for ticks daily, and prompt removal of attached ticks

before transmission of these microorganisms can occur (B-III)

(see table 1 for recommendation categories, which are indicated

in parentheses throughout this text).

For prevention of Lyme disease after a recognized tick bite,

routine use of antimicrobial prophylaxis or serologic testing is

not recommended (E-III). A single dose of doxycycline may

be offered to adult patients (200 mg dose) and to children �8

years of age (4 mg/kg up to a maximum dose of 200 mg) (B-

I) when all of the following circumstances exist: (a) the attached

tick can be reliably identified as an adult or nymphal I. sca-

pularis tick that is estimated to have been attached for �36 h

on the basis of the degree of engorgement of the tick with

blood or of certainty about the time of exposure to the tick;

(b) prophylaxis can be started within 72 h of the time that the

tick was removed; (c) ecologic information indicates that the

local rate of infection of these ticks with B. burgdorferi is �20%;

and (d) doxycycline treatment is not contraindicated. The time

limit of 72 h is suggested because of the absence of data on

the efficacy of chemoprophylaxis for tick bites following tick

removal after longer time intervals. Infection of �20% of ticks

with B. burgdorferi generally occurs in parts of New England,

in parts of the mid-Atlantic States, and in parts of Minnesota

and Wisconsin, but not in most other locations in the United

States. Whether use of antibiotic prophylaxis after a tick bite

will reduce the incidence of HGA or babesiosis is unknown.

Doxycycline is relatively contraindicated in pregnant women

and children !8 years old. The panel does not believe that

amoxicillin should be substituted for doxycycline in persons

for whom doxycycline prophylaxis is contraindicated because

of the absence of data on an effective short-course regimen for

prophylaxis, the likely need for a multiday regimen (and its

associated adverse effects), the excellent efficacy of antibiotic

treatment of Lyme disease if infection were to develop, and the

extremely low risk that a person with a recognized bite will

develop a serious complication of Lyme disease (D-III).

Prophylaxis after I. pacificus bites is generally not necessary,

because rates of infection with B. burgdorferi in these ticks are

low in almost the entire region in which the tick is endemic.

However, if a higher infection rate were documented in specific

local areas (�20%), prophylaxis with single-dose doxycycline

would be justified if the other criteria mentioned above are

met.

To prescribe antibiotic prophylaxis selectively to prevent

Lyme disease, health care practitioners in areas of endemicity

should learn to identify I. scapularis ticks, including its stages

(figure 1), and to differentiate ticks that are at least partially

engorged with blood (figure 2A and 2B) (A-III). Testing of ticks

for tickborne infectious agents is not recommended, except in

research studies (D-II).

Health care practitioners, particularly those in areas of en-

demicity, should become familiar with the clinical manifesta-

tions and recommended practices for diagnosing and treating

Lyme disease, HGA, and babesiosis (A-III). Persons who have

removed attached ticks from themselves (including those who

have received antibiotic prophylaxis) should be monitored

closely for signs and symptoms of tickborne diseases for up to

30 days; in particular, they should be monitored for the de-

velopment of an expanding skin lesion at the site of the tick

bite (erythema migrans) that may suggest Lyme disease. Persons

who develop a skin lesion or viral infection–like illness within


Figure 1. From left to right, an Ixodes scapularis larva, nymph, adultmale tick, and adult female tick. The picture is a generous gift from Dr.Richard Falco (Fordham University).

1 month after removing an attached tick should promptly seek

medical attention to assess the possibility of having acquired a

tickborne infection. HGA and babesiosis should be included

in the differential diagnosis of patients who develop fever after

an Ixodes tick bite in an area where these infections are endemic

(A-II). A history of having received the previously licensed

recombinant outer surface protein A (OspA) Lyme disease vac-

cine preparation should not alter the recommendations above;

the same can be said for having had a prior episode of early

Lyme disease.

Early Lyme Disease

Erythema migrans. Doxycycline (100 mg twice per day),

amoxicillin (500 mg 3 times per day), or cefuroxime axetil (500

mg twice per day) for 14 days (range, 10–21 days for doxy-

cycline and 14–21 days for amoxicillin or cefuroxime axetil) is

recommended for the treatment of adult patients with early

localized or early disseminated Lyme disease associated with

erythema migrans, in the absence of specific neurologic man-

ifestations (see Lyme meningitis, below) or advanced atrioven-

tricular heart block (A-I). Each of these antimicrobial agents

has been shown to be highly effective for the treatment of

erythema migrans and associated symptoms in prospective

studies. Doxycycline has the advantage of being effective for

treatment of HGA (but not for babesiosis), which may occur

simultaneously with early Lyme disease. Doxycycline is rela-

tively contraindicated during pregnancy or lactation and in

children !8 years of age. Antibiotics recommended for children

are amoxicillin (50 mg/kg per day in 3 divided doses [maximum

of 500 mg per dose]), cefuroxime axetil (30 mg/kg per day in

2 divided doses [maximum of 500 mg per dose]), or, if the

patient is �8 years of age, doxycycline (4 mg/kg per day in 2

divided doses [maximum of 100 mg per dose]) (A-II).

Macrolide antibiotics are not recommended as first-line ther-

apy for early Lyme disease, because those macrolides that have

been compared with other antimicrobials in clinical trials have

been found to be less effective (E-I). When used, they should

be reserved for patients who are intolerant of, or should not

take, amoxicillin, doxycycline, and cefuroxime axetil. For adults

with these limitations, recommended dosage regimens for mac-

rolide antibiotics are as follows: azithromycin, 500 mg orally

per day for 7–10 days; clarithromycin, 500 mg orally twice per

day for 14–21 days (if the patient is not pregnant); or eryth-

romycin, 500 mg orally 4 times per day for 14–21 days. The

recommended dosages of these agents for children are as fol-

lows: azithromycin, 10 mg/kg per day (maximum of 500 mg

per day); clarithromycin, 7.5 mg/kg twice per day (maximum

of 500 mg per dose); or erythromycin, 12.5 mg/kg 4 times per

day (maximum of 500 mg per dose). Patients treated with

macrolides should be closely observed to ensure resolution of

the clinical manifestations.

First-generation cephalosporins, such as cephalexin, are in-

effective for treatment of Lyme disease and should not be used

(E-II). When erythema migrans cannot be reliably distin-

guished from community-acquired bacterial cellulitis, a rea-

sonable approach is to treat with either cefuroxime axetil or

amoxicillin–clavulanic acid (dosage of amoxicillin–clavulanic

acid for adults, 500 mg 3 times per day; dosage for children,

50 mg/kg per day in 3 divided doses [maximum of 500 mg per

dose]), because these antimicrobials are generally effective

against both types of infection (A-III).

Ceftriaxone, while effective, is not superior to oral agents

and is more likely than the recommended orally administered

antimicrobials to cause serious adverse effects. Therefore, cef-

triaxone is not recommended for treatment of patients with

early Lyme disease in the absence of neurologic involvement

or advanced atrioventricular heart block (E-I).

Lyme meningitis and other manifestations of early neuro-

logic Lyme disease. The use of ceftriaxone (2 g once per day

intravenously for 14 days; range, 10–28 days) in early Lyme

disease is recommended for adult patients with acute neurologic

disease manifested by meningitis or radiculopathy (B-I). Par-

enteral therapy with cefotaxime (2 g intravenously every 8 h)

or penicillin G (18–24 million U per day for patients with

normal renal function, divided into doses given every 4 h), may

be a satisfactory alternative (B-I). For patients who are intol-

erant of b-lactam antibiotics, increasing evidence indicates that

doxycycline (200–400 mg per day in 2 divided doses orally for

10–28) days may be adequate (B-I). Doxycycline is well ab-

sorbed orally; thus, intravenous administration should only

rarely be needed.

For children, ceftriaxone (50–75 mg/kg per day) in a single


Figure 2. Ixodes scapularis ticks demonstrating changes in blood engorgement after various durations of attachment. A, Nymphal stage (reprintedfrom [1], with permission from Elsevier). B, Adult stage. The pictures are a generous gift from Dr. Richard Falco (Fordham University).

daily intravenous dose (maximum, 2 g) (B-I) is recommended.

An alternative is cefotaxime (150–200 mg/kg per day) divided

into 3 or 4 intravenous doses per day (maximum, 6 g per day)

(B-II) or penicillin G (200,000–400,000 units/kg per day; max-

imum, 18–24 million U per day) divided into doses given in-

travenously every 4 h for those with normal renal function (B-

I). Children �8 years of age have also been successfully treated

with oral doxycycline at a dosage of 4–8 mg/kg per day in 2

divided doses (maximum, 100–200 mg per dose) (B-II).

Although antibiotic treatment may not hasten the resolution

of seventh cranial nerve palsy associated with B. burgdorferi

infection, antibiotics should be given to prevent further se-

quelae (A-II). Cranial nerve palsies in patients with Lyme dis-

ease are often associated with a lymphocytic CSF pleocytosis,

with or without symptoms of meningitis. Panel members dif-

fered in their approach to the neurologic evaluation of patients

with Lyme disease–associated seventh cranial nerve palsy. Some

perform a CSF examination on all such patients. Others do not


because of the good clinical response with orally administered

antibiotics (even in the presence of CSF pleocytosis) and the

absence of evidence of recurrent CNS disease in these patients.

There was agreement that lumbar puncture is indicated for

those in whom there is strong clinical suspicion of CNS in-

volvement (e.g., severe or prolonged headache or nuchal ri-

gidity). Patients with normal CSF examination findings and

those for whom CSF examination is deemed unnecessary be-

cause of lack of clinical signs of meningitis may be treated with

a 14-day course (range, 14–21 days) of the same antibiotics

used for patients with erythema migrans (see above) (B-III).

Those with both clinical and laboratory evidence of CNS in-

volvement should be treated with regimens effective for Lyme

meningitis, as described above (B-III).

Lyme carditis. Patients with atrioventricular heart block

and/or myopericarditis associated with early Lyme disease may

be treated with either oral or parenteral antibiotic therapy for

14 days (range, 14–21 days). Hospitalization and continuous

monitoring are advisable for symptomatic patients, such as

those with syncope, dyspnea, or chest pain. It is also recom-

mended for patients with second- or third-degree atrioven-

tricular block, as well as for those with first-degree heart block

when the PR interval is prolonged to �30 milliseconds, because

the degree of block may fluctuate and worsen very rapidly in

such patients.

A parenteral antibiotic, such as ceftriaxone, is recommended

as initial treatment of hospitalized patients (see recommen-

dations for treatment of Lyme meningitis above) (B-III). For

patients with advanced heart block, a temporary pacemaker

may be required; expert consultation with a cardiologist is rec-

ommended. Use of the pacemaker may be discontinued when

the advanced heart block has resolved. An oral antibiotic treat-

ment regimen should be used for completion of therapy and

for outpatients, as is used for patients with erythema migrans

without carditis (see above) (B-III).

Borrelial lymphocytoma. Available data indicate that bor-

relial lymphocytoma may be treated with the same regimens used

to treat patients with erythema migrans (see above) (B-II).

Pregnancy. Pregnant and lactating patients may be treated

in a fashion identical to nonpregnant patients with the same

disease manifestation, except that doxycycline should be

avoided (B-III).

Late Lyme Disease

Lyme arthritis. Lyme arthritis can usually be treated suc-

cessfully with antimicrobial agents administered orally. Doxy-

cycline (100 mg twice per day) (B-I), amoxicillin (500 mg 3

times per day) (B-I), or cefuroxime axetil (500 mg twice per

day) (B-III) for 28 days is recommended for adult patients

without clinical evidence of neurologic disease. For children,

amoxicillin (50 mg/kg per day in 3 divided doses [maximum

of 500 mg per dose]) (B-I), cefuroxime axetil (30 mg/kg per

day in 2 divided doses [maximum of 500 mg per dose]) (B-

III), or, if the patient is �8 years of age, doxycycline (4 mg/

kg per day in 2 divided doses [maximum of 100 mg per dose])

(B-I) is recommended. Oral antibiotics are easier to administer

than intravenous antibiotics, are associated with fewer serious

complications, and are considerably less expensive. However,

it is important to recognize that a small number of patients

treated with oral agents have subsequently manifested overt

neuroborreliosis, which may require intravenous therapy with

a b-lactam antibiotic (see the paragraph below) for successful

resolution. Further controlled trials are needed to compare the

safety and efficacy of oral versus intravenous therapy for Lyme

arthritis.

Neurologic evaluation that may include lumbar puncture

should be performed for patients in whom there is a clinical

suspicion of neurologic involvement. Adult patients with ar-

thritis and objective evidence of neurologic disease should

receive parenteral therapy with ceftriaxone (A-II) for 2–4

weeks. Cefotaxime or penicillin G administered parenterally

is an acceptable alternative (B-II). For children, intravenous

ceftriaxone or intravenous cefotaxime is recommended (B-

III); penicillin G administered intravenously is an alternative

(B-III). See the recommendations above for treatment of pa-

tients with Lyme meningitis for suggested doses of each of

these antimicrobials.

For patients who have persistent or recurrent joint swelling

after a recommended course of oral antibiotic therapy, we rec-

ommend re-treatment with another 4-week course of oral an-

tibiotics or with a 2–4-week course of ceftriaxone IV (B-III)

(for dosages of oral agents, see the recommendations above for

treatment of erythema migrans, and for dosages of parenteral

agents, see the recommendations above for treatment of Lyme

meningitis). A second 4-week course of oral antibiotic therapy

is favored by panel members for the patient whose arthritis has

substantively improved but has not yet completely resolved,

reserving intravenous antibiotic therapy for those patients

whose arthritis failed to improve at all or worsened. Clinicians

should consider waiting several months before initiating re-

treatment with antimicrobial agents because of the anticipated

slow resolution of inflammation after treatment. If patients

have no resolution of arthritis despite intravenous therapy and

if PCR results for a sample of synovial fluid (and synovial tissue

if available) are negative, symptomatic treatment is recom-

mended (B-III). Symptomatic therapy might consist of non-

steroidal anti-inflammatory agents, intra-articular injections of

corticosteroids, or disease-modifying antirheumatic drugs

(DMARDs), such as hydroxychloroquine; expert consultation

with a rheumatologist is recommended. If persistent synovitis

is associated with significant pain or limitation of function,


arthroscopic synovectomy may reduce the duration of joint

inflammation (B-II).

Late neurologic Lyme disease. Adult patients with late neu-

rologic disease affecting the central or peripheral nervous sys-

tem should be treated with intravenous ceftriaxone for 2 to 4

weeks (B-II). Cefotaxime or penicillin G administered intra-

venously is an alternative (B-II). Response to treatment is usu-

ally slow and may be incomplete. Re-treatment is not rec-

ommended unless relapse is shown by reliable objective

measures. Ceftriaxone is also recommended for children with

late neurologic Lyme disease (B-II). Cefotaxime or penicillin

G administered intravenously is an alternative (B-III). See the

recommendations above on the treatment of Lyme meningitis

for suggested doses of each of these antimicrobials.

Acrodermatitis chronica atrophicans. Available data in-

dicate that acrodermatitis chronica atrophicans may be treated

with a 21-day course of the same antibiotics (doxycycline [B-

II], amoxicillin [B-II], and cefuroxime axetil [B-III]) used to

treat patients with erythema migrans (see above). A controlled

study is warranted to compare oral with parenteral antibiotic

therapy for the treatment of acrodermatitis chronica

atrophicans.

Coinfection. Coinfection with B. microti or A. phagocyto-

philum or both may occur in patients with early Lyme disease

(usually in patients with erythema migrans) in geographic areas

where these pathogens are endemic. Coinfection should be con-

sidered in patients who present with more-severe initial symp-

toms than are commonly observed with Lyme disease alone,

especially in those who have high-grade fever for 148 h, despite

receiving antibiotic therapy appropriate for Lyme disease, or

who have unexplained leukopenia, thrombocytopenia, or ane-

mia (A-III). Coinfection might also be considered in the sit-

uation in which there has been resolution of the erythema

migrans skin lesion but either no improvement or worsening

of viral infection–like symptoms (B-III).

Post–Lyme Disease Syndromes

There is no well-accepted definition of post–Lyme disease syn-

drome. This has contributed to confusion and controversy and

to a lack of firm data on its incidence, prevalence, and path-

ogenesis. In an attempt to provide a framework for future

research on this subject and to reduce diagnostic ambiguity in

study populations, a definition for post–Lyme disease syndrome

is proposed in these guidelines. Whatever definition is even-

tually adopted, having once had objective evidence of B. burg-

dorferi infection must be a condition sine qua non. Further-

more, when laboratory testing is done to support the original

diagnosis of Lyme disease, it is essential that it be performed

by well-qualified and reputable laboratories that use recom-

mended and appropriately validated testing methods and in-

terpretive criteria. Unvalidated test methods (such as urine an-

tigen tests or blood microscopy for Borrelia species) should not

be used.

There is no convincing biologic evidence for the existence

of symptomatic chronic B. burgdorferi infection among patients

after receipt of recommended treatment regimens for Lyme

disease. Antibiotic therapy has not proven to be useful and is

not recommended for patients with chronic (�6 months) sub-

jective symptoms after recommended treatment regimens for

Lyme disease (E-I).

Therapeutic modalities not recommended. Because of a

lack of biologic plausibility, lack of efficacy, absence of sup-

porting data, or the potential for harm to the patient, the

following are not recommended for treatment of patients with

any manifestation of Lyme disease: first-generation cephalo-

sporins, fluoroquinolones, carbapenems, vancomycin, metro-

nidazole, tinidazole, amantadine, ketolides, isoniazid, trimeth-

oprim-sulfamethoxazole, fluconazole, benzathine penicillin G,

combinations of antimicrobials, pulsed-dosing (i.e., dosing on

some days but not others), long-term antibiotic therapy, anti-

Bartonella therapies, hyperbaric oxygen, ozone, fever therapy,

intravenous immunoglobulin, cholestyramine, intravenous hy-

drogen peroxide, specific nutritional supplements, and others

(see table 4) (E-III).

HGA

All symptomatic patients suspected of having HGA should be

treated with antimicrobial therapy because of the risk of com-

plications (A-III). Suspicion of HGA is based on the acute onset

of unexplained fever, chills, and headache, often in association

with thrombocytopenia, leukopenia, and/or increased liver en-

zyme levels in patients with exposure to I. scapularis or I. pa-

cificus ticks within the prior 3 weeks. Confirmation of the di-

agnosis is based on laboratory testing (see the HGA section of

the text), but antibiotic therapy should not be delayed in a

patient with a suggestive clinical presentation pending the re-

sults. Identification of the characteristic intragranulocytic in-

clusions on blood smear is the most rapid diagnostic method,

but such inclusions are often scant in number or sometimes

absent; in addition, other types of inclusions unrelated to HGA

or overlying platelets can be misinterpreted by inexperienced

observers. Testing for antibodies to A. phagocytophilum is the

most sensitive diagnostic method, but only if a convalescent-

phase serum sample is assayed.

Doxycycline is recommended as the treatment of choice for

patients who are suspected of having symptomatic HGA (A-

II). The dosage regimen for adults is 100 mg given twice per

day by mouth (or intravenously for those patients unable to

take an oral medication) for 10 days. This treatment regimen

should be adequate therapy for patients with HGA alone and

for patients who have coinfection with B. burgdorferi. Persis-

tence of fever for 148 h after initiation of doxycycline treatment


suggests that the diagnosis of HGA is incorrect or, more re-

motely, that the patient may be coinfected with B. microti.

Although a 10-day treatment course of doxycycline may be

offered to all children as well (C-III), the panel preferred a

modified approach in which severity of illness, age of the child,

and the presence or absence of coinfection with B. burgdorferi

were each considered, to minimize an already low risk of drug

toxicity. The suggested dosage of doxycycline for children with

HGA is 4 mg/kg per day in 2 divided doses (maximum of 100

mg per dose) given orally (or intravenously for children unable

to take an oral medication). Children �8 years of age may be

treated with a 10-day course of doxycycline. For severely ill

children !8 years of age without concomitant Lyme disease,

the panel recommended an abbreviated treatment course of 4–

5 days (i.e., for ∼3 days after resolution of fever) (B-III). Chil-

dren treated with an abbreviated course of therapy should be

closely observed to ensure resolution of clinical and laboratory

abnormalities. If the child has concomitant Lyme disease, then

amoxicillin (50 mg/kg per day in 3 divided doses [maximum

of 500 mg per dose]) or cefuroxime axetil (30 mg/kg per day

in 2 divided doses [maximum of 500 mg per dose]) should be

initiated at the conclusion of the course of doxycycline to com-

plete a 14-day total course of antibiotic therapy (B-III).

Patients with mild illness due to HGA who are not optimally

suited for doxycycline treatment because of a history of drug

allergy, pregnancy, or age !8 years, may be treated with rifampin

for 7–10 days using a dosage regimen of 300 mg twice per day

by mouth for adults and 10 mg/kg twice per day for children

(maximum of 300 mg per dose) (B-III). Rifampin-treated pa-

tients should be closely observed to ensure resolution of clinical

and laboratory abnormalities. Because rifampin is not effective

therapy for Lyme disease, patients coinfected with B. burgdorferi

should also be treated with amoxicillin or cefuroxime axetil, as

used for the treatment of erythema migrans (see above) (A-I).

No other antimicrobial can be recommended for the treatment

of HGA (E-III).

Treatment is not recommended for asymptomatic individuals

who are seropositive for antibodies to A. phagocytophilum (E-

III).

Babesiosis

All patients with active babesiosis should be treated with an-

timicrobials because of the risk of complications (A-III). Di-

agnostic criteria for active babesial infection should include the

presence of viral infection–like symptoms and identification of

babesial parasites in blood by smear evaluation or by PCR

amplification of babesial DNA. Symptomatic patients whose

serum contains antibody to babesia but whose blood lacks iden-

tifiable babesial parasites on smear or babesial DNA by PCR

should not receive treatment (E-III). Treatment is also not rec-

ommended for asymptomatic individuals, regardless of the re-

sults of serologic examination, blood smears, or PCR (E-III).

Asymptomatic patients with positive babesial smears and/or

PCR should have these studies repeated, and a course of treat-

ment should be considered if parasitemia persists for 13 months

(B-III).

The combination of either atovaquone plus azithromycin or

clindamycin plus quinine for 7–10 days is the initial therapy

that should be considered for patients with babesiosis (A-I).

Clindamycin and quinine should be given for those with severe

babesiosis (A-III). In such patients, clindamycin should be ad-

ministered intravenously rather than orally, and exchange trans-

fusion should be considered. Longer duration of antimicrobial

therapy may be necessary in highly and persistently symptom-

atic patients until parasitemia is cleared, but no controlled stud-

ies exist that define the risk-benefit ratio of more prolonged

therapy.

The dosage regimen of atovaquone plus azithromycin for

adults is atovaquone, 750 mg orally every 12 h, and azithro-

mycin, 500–1000 mg on day 1 and 250 mg orally once per day

thereafter. For immunocompromised patients with babesiosis,

higher doses of azithromycin (600–1000 mg per day) may be

used. The dosages for children are atovaquone, 20 mg/kg every

12 h (up to a maximum of 750 mg per dose), and azithromycin,

10 mg/kg once per day on day 1 (up to a maximum of 500

mg per dose) and 5 mg/kg once per day (up to a maximum

of 250 mg per dose) orally thereafter.

The dosage regimen of clindamycin plus quinine for adults

is clindamycin, 300–600 mg every 6 h intravenously or 600 mg

every 8 h orally, and quinine, 650 mg every 6–8 h orally. Dosages

for children are clindamycin, 7–10 mg/kg given intravenously

or orally every 6–8 h (up to a maximum of 600 mg per dose)

and quinine 8 mg/kg given orally every 8 h (up to a maximum

of 650 mg per dose).

Partial or complete RBC exchange transfusion is indicated

for persons with severe babesiosis, as indicated by high-grade

parasitemia (�10%), significant hemolysis, or renal, hepatic,

or pulmonary compromise (A-III). No data are available to

determine whether partial exchange transfusion is preferable

to whole blood exchange; expert consultation with an infectious

diseases expert and a hematologist is recommended.

Patients with moderate-to-severe babesiosis should be mon-

itored closely during therapy to ensure clinical improvement

and improvement of parasitemia and other laboratory abnor-

malities (A-III). In patients with mild-to-moderate babesiosis,

clinical improvement should occur within 48 h after the start

of antiprotozoal therapy, and symptoms should completely re-

solve within 3 months after the initiation of therapy. In severely

ill patients, the hematocrit and percentage of parasitized eryth-

rocytes should be monitored daily or every other day until the

patient has improved and the level of parasitemia has decreased

to !5% of erythrocytes. Some patients may have persistence of


low-grade parasitemia for months after specific antimicrobial

therapy.

Physicians should consider the possibility of coinfection with

B. burgdorferi or A. phagocytophilum or both in patients with

especially severe or persistent symptoms, despite administration

of appropriate anti-babesial therapy (A-III). Patients found to

have coinfection should be treated with additional antimicro-

bial therapy, as described above. An underlying immunodefi-

ciency (including asplenia or prior splenectomy, malignancy,

or HIV infection) also should be considered in patients with

severe or prolonged episodes of babesiosis.

Re-treatment of patients with antibabesial therapy, as out-

lined above, should be considered if babesial parasites or am-

plifiable babesial DNA are detected in blood �3 months after

initial therapy, regardless of symptom status (A-III). However,

such assays need not be done routinely for immunocompetent

patients who are asymptomatic.

OBJECTIVE

The objectives of these practice guidelines are to provide cli-

nicians and other health care practitioners with recommen-

dations for treatment of patients in the United States with

suspected or established Lyme disease, HGA (formerly known

as human granulocytic ehrlichiosis), or babesiosis. In addition,

recommendations are provided for prevention of these infec-

tions, all of which may be transmitted by certain species of

Ixodes ticks. The panel performed an extensive review of all of

the randomized, controlled trials and open-label trials pub-

lished in peer-reviewed, English-language journals. Previously

published and widely accepted criteria were used to grade the

quality of the evidence on which the recommendations were

based (table 1) [2, 3].

Lyme disease, caused by the spirochete B. burgdorferi, is en-

demic in several regions of the United States, particularly areas

of the Northeast, upper Midwest, and northern California [4,

5]. It is the most frequently reported vectorborne disease in

the United States. The Ixodes tick vectors have a 3-stage life

cycle: larva, nymph, and adult. The risk of human illness is

highest during the time of year when the nymphal stage is

seeking a blood meal. The most common clinical manifestation

of Lyme disease is a skin lesion called erythema migrans that

results from cutaneous infection with B. burgdorferi. Adults and

children of both sexes may be affected. Patients with Lyme

disease are evaluated and treated by general practitioners, pe-

diatricians, and internists, as well as by infectious diseases

specialists, dermatologists, rheumatologists, neurologists, car-

diologists, orthopedists, gynecologists and obstetricians, oto-

laryngologists, and ophthalmologists. Because of the differences

in the species of Borrelia that cause Lyme disease in North

America (B. burgdorferi), compared with those that cause this

infection in Eurasia (B. burgdorferi, Borrelia afzelii, and Borrelia

garinii), recommendations were based, whenever possible, on

studies conducted in the United States. In the treatment of

Lyme disease, as in all infectious diseases, basic medical and

scientific principles should be considered. In selecting an an-

tibiotic, there should be evidence of activity in vitro, evidence

for penetration into the infected sites, and well-designed clinical

studies to support the treatment regimen.

RECOMMENDATIONS FOR THE CLINICALASSESSMENT, TREATMENT, AND PREVENTIONOF LYME DISEASE, HGA, AND BABESIOSIS

PREVENTION OF TICK BITES

The best currently available method for preventing infection

with B. burgdorferi and other Ixodes-transmitted infections is

to avoid tick-infested areas [6]. If exposure to either I. scapularis

or I. pacificus ticks is unavoidable, a number of measures may

help to decrease the risk that ticks will attach and subsequently

transmit infection. Frequent visual inspection of skin and

clothes may help to identify ticks prior to attachment, thus

allowing removal before infection can be transmitted. Attached

ticks should be removed promptly, preferably with the aid of

fine-tip forceps [7]. If a portion of the mouth parts of the tick

remains embedded in the skin, only topical disinfection of the

site is suggested, because attempts to remove this material can

cause tissue damage and are unnecessary as the risk of Lyme

disease is unaffected.

Use of protective clothing (long-sleeved shirt tucked into

pants and long pants tucked into socks) may interfere with tick

attachment by increasing the time required for ticks to find

exposed skin, thus facilitating their recognition and removal.

Wearing light-colored clothing to provide a background that

contrasts with the tick is often recommended as a common

sense precaution to enhance the ability to see and remove ticks

before attachment. A recent study, however, suggested that an

Ixodes tick species present in Europe (Ixodes ricinus) may be

more attracted to light-colored than darker-colored clothing

[8]. These findings require confirmation before any change in

recommended practice should be considered.

Tick and insect repellents that contain N,N-diethyl-3-meth-

ylbenzamide (DEET) applied to the skin or clothing provide

additional protection but may require reapplication for max-

imum effectiveness. The timing of reapplication depends on

the specific preparation utilized [9–11]. Ticks detect DEET

through olfactory sensing and are repelled [12]. Serious neu-

rologic complications in children after excessive application of

DEET-containing repellents have been reported [13], but the

compound appears to be safe when used as directed in the

product labels, even for young children 12 months old [14,15].

DEET need not be applied to the face or hands for prevention

of tick bites and should not be applied to skin that is either


irritated or abraded. After returning indoors, skin that was

treated with DEET should be washed with soap and water.

Permethrin (a synthetic pyrethrin) is available in a spray solely

for application to clothing (it is inactivated by skin lipids [16])

and is particularly effective because it kills ticks on contact

[17]. Picaridin and IR3535 have recently been promoted as

effective insect repellents, but their effectiveness against Ixodes

ticks has not been determined [14, 18].

To date there is only limited evidence that any of the personal

protective measures described above are effective in reducing

the number of human cases of Lyme disease [19–22].

PROPHYLAXIS OF LYME DISEASE

Primary Management Options Considered

For persons who remove attached ticks, the management op-

tions considered included treating with antimicrobials: (1) all

persons, (2) only persons believed to be at increased risk of

developing Lyme disease (e.g., those removing a nymphal or

adult I. scapularis or I. pacificus tick after at least 36 h of at-

tachment), (3) only persons who develop erythema migrans or

other clinical signs and symptoms of a tickborne infection, and

(4) all persons who seroconvert from a negative to a positive

test result for serum antibodies to B. burgdorferi. Management

of bites by the vector ticks I. ricinus and Ixodes persulcatus was

not considered by the panel, because these tick species are not

present in North America.

Outcomes Evaluated

The panel weighed both the risks and consequences of devel-

oping Lyme disease (including the risk of late complications)

in persons bitten by I. scapularis or I. pacificus ticks against the

economic costs and adverse effects of prophylactic antimicro-

bials. The impact of the different strategies on quality of life

was considered. In addition, the potential effect of having pre-

viously received the recombinant OspA Lyme vaccine, which

was withdrawn by the manufacturer in 2002, was considered

[23]. The principal desired outcome is prevention of Lyme

disease. Another desired outcome is the prevention of other

Ixodes-transmitted illnesses, including HGA (caused by A. phag-

ocytophilum) and babesiosis. Either of the latter 2 infections

may occur alone or in conjunction with Lyme disease, and

occasionally all 3 infections may occur together [24–28].

Options Considered and Evidence To Support Recommendations

Option 1: antimicrobial therapy for all persons who remove

vector ticks (I. scapularis or I. pacificus) that have become

attached. Tick bites are extremely common in areas of en-

demicity. For example, it has been estimated that nearly 180,000

tick bites occurred annually in Westchester County, New York

(total population, ∼850,000), during the 1991–1994 time period

[29]. In a prospective study in which individuals from this

county were closely observed after a documented I. scapularis

tick bite, a second bite occurred in ∼15% of patients within

just 6 weeks of the original bite [30].

Three randomized, prospective studies on the use of anti-

biotic chemoprophylaxis were reported through 1993 [31–33].

In each study, a 10-day course of antibiotics was compared

with an identical-appearing placebo. Although none of the an-

tibiotic-treated patients developed Lyme disease in these trials,

the studies were not adequately powered to show a significant

difference in efficacy compared with placebo. Thus, it remained

unclear whether the use of antibiotics for prophylaxis after I.

scapularis tick bites could actually cure incubating B. burgdorferi

infection [34]. In a larger and more recent chemoprophylaxis

trial, erythema migrans at the site of a tick bite developed in

only 1 (0.4%) of 235 subjects who received a single 200-mg

dose of doxycycline within 72 h of removing an attached I.

scapularis tick, compared with 8 (3.2%) of 247 subjects who

received placebo ( ) [30]. None of the subjects developedP ! .04

either objective evidence of extracutaneous Lyme disease or

asymptomatic B. burgdorferi infection. Treatment efficacy was

87%, but there was a wide 95% CI (25%–98%), reflecting the

small number of patients who developed Lyme disease. Al-

though single-dose doxycycline was frequently associated with

gastrointestinal upset, such as nausea or vomiting [30], the

authors cited data to show that the tolerability could be im-

proved by administration with food with only a minimal de-

crease in peak serum concentrations [35].

A proof-of-concept study in mice bitten by infected I. sca-

pularis ticks confirmed that a single oral dose of doxycycline

is effective for prevention of B. burgdorferi infection [36]. Al-

though the efficacy rate was lower in the mouse study (43%),

the time that the concentration of doxycycline remained above

the MIC (T1MIC) of B. burgdorferi in the mouse model was

less than one-half the estimated T1MIC in humans after receipt

of a single 200-mg dose of doxycycline because of a faster rate

of elimination of doxycycline in mice than in humans [30, 36,

37]. Indeed, parenteral administration of a single dose of a

sustained release preparation of doxycycline in the same mouse

model was 100% effective in prevention of B. burgdorferi in-

fection [36].

One cost-effectiveness analysis concluded that a 2-week

course of doxycycline is indicated when the probability of in-

fection with B. burgdorferi after a tick bite is �3.6% and should

be considered when the theoretical probability ranges from 1%

to 3.5% [38]. Some experts disagree with key assumptions in

the model (many of which tended to favor the use of anti-

microbial prophylaxis) and consider the duration of treatment

to be excessive. However, the findings do argue against routine

prophylaxis of all I. scapularis tick bites, because the frequency

of Lyme disease was !3.6% among placebo recipients in each

of the 4 reported chemoprophylaxis trials [30–33].


Doxycycline is relatively contraindicated for women who are

either pregnant or breast-feeding, as well as for children !8

years of age. In these patients, if chemoprophylaxis were to be

used, an alternative antimicrobial, such as amoxicillin, would

need to be considered. Amoxicillin is effective against B. burg-

dorferi both in vitro [39, 40] and in clinical trials of patients

with Lyme disease [41–44], and it may be expected to be a

useful prophylactic agent after a bite from an I. scapularis or

I. pacificus tick. No cases of Lyme disease developed in 192

patients given 10 days of amoxicillin for prophylaxis after a

bite from an I. scapularis tick in a randomized clinical trial

[32], although failure of amoxicillin prophylaxis has been re-

ported anecdotally from Europe [45]. Amoxicillin has a shorter

half-life than doxycycline, and a multiday regimen would likely

be necessary for prophylaxis to be effective [37].

Some practitioners prescribe a 10–14-day course of pro-

phylactic amoxicillin for pregnant women after I. scapularis

tick bites, because case reports have suggested that Lyme dis-

ease during pregnancy may be associated with adverse out-

comes for the fetus [46]. However, a large body of data from

clinical and epidemiologic studies suggest that favorable out-

comes can be expected when pregnant women with Lyme

disease are treated with standard antibiotic regimens [47–49].

Indeed, there is little evidence that a congenital Lyme disease

syndrome occurs [50, 51].

It has been estimated that if a 10-day course of amoxicillin

were routinely used for antibiotic prophylaxis after tick bites,

8 cases of drug-associated rash, including 1 severe life-threat-

ening reaction, would occur for every 10 cases of early Lyme

disease that were prevented [34]. In addition, 3 cases of minor

amoxicillin-related adverse effects (e.g., diarrhea) would occur

for every case of Lyme disease that was prevented. In 2 studies

of prophylaxis for tick bites in which 10 days of an antimicrobial

preparation was prescribed, the risk of acquiring Lyme disease

after a tick bite among placebo recipients was approximately

the same as the risk of developing a rash from the prophylactic

antibiotic [31, 32].

In addition to B. burgdorferi, other potential pathogens, such

as A. phagocytophilum or B. microti, may also be transmitted

by Ixodes ticks [52, 53]. Doxycycline is effective for the treat-

ment of patients with HGA (see the section on HGA below)

but is not effective therapy for babesiosis (see the section on

babesiosis below). There are no published clinical data on the

efficacy of prophylaxis with doxycycline against either of these

microorganisms. Amoxicillin is not active against either A.

phagocytophilum or B. microti and, therefore, would be expected

to be ineffective for prevention of these infections.

The prevalence of B. burgdorferi in nymphal I. scapularis ticks

commonly ranges between 20% and 40% in areas of endemicity

in the Northeastern and upper Midwestern United States [54–

56]. However, I. pacificus ticks (the vector for Lyme disease in

the western United States) have a much lower infection rate

with B. burgdorferi (0%–14%) [57]. This is presumably because

most I. pacificus ticks feed on lizards, the blood of which is

bactericidal for B. burgdorferi [57–59].

The prevalence of B. burgdorferi infection in host seeking I.

scapularis ticks in the southern United States is also extremely

low; for adult stage ticks, it is 0%–4.6% [60–62], and for

nymphal stage ticks, evidence of infection has not been found

to date [63]. The panel is unaware of a proven case of B.

burgdorferi infection acquired indigenously in any state south

of Maryland or Virginia [64]. Patients in the southern United

States may develop an erythema migrans–like skin lesion as-

sociated with mild viral infection-like symptoms resembling

Lyme disease following a bite of an Amblyomma americanum

(Lone star) tick [65]. Although 1 report associated this illness,

known as Southern tick–associated rash illness (STARI), with

Borrelia lonestari infection [66], most cases do not appear to

be caused by any known Borrelia species [67].

Option 2: antimicrobial therapy only for persons believed

to be at high risk for Lyme disease (e.g., those removing a

nymphal or adult I. scapularis tick after �36 h of attachment).

Several factors associated with risk of developing Lyme disease

after a tick bite can be identified. The lower risk from Ixodes

tick bites in the western and southern United States has been

discussed above. Regardless of the geographic region, larval I.

scapularis and I. pacificus ticks are rarely infected with B. burg-

dorferi. Larval ticks become infected after feeding on an infected

animal, rather than from transovarial transmission, and they

feed only once before molting to the nymphal stage. Therefore,

larval ticks do not serve as relevant vectors for Lyme disease.

Unengorged nymphal or adult Ixodes ticks also pose little or

no risk of transmission of B. burgdorferi. The duration of tick

attachment can be estimated on the basis of a measurement of

the degree of tick engorgement with blood (scutal index) [30,

68, 69]. In the single-dose doxycycline chemoprophylaxis trial,

duration of tick attachment as assessed by this measure cor-

related directly with risk of developing Lyme disease. Erythema

migrans developed at the tick bite site in 8 (9.9%) of 81 placebo-

treated subjects bitten by an I. scapularis nymphal tick that had

at least some blood engorgement. The risk increased to 3 (25%)

of 12 if the tick were highly engorged, equating to a �72-h

duration of attachment, compared with 0 (0%) of 59 for bites

from nymphal ticks with no blood engorgement ( andP p .02

, respectively) [30]. In a separate study from New YorkP p .004

State, the risk of developing B. burgdorferi infection was 20%

(3 of 15) among patients bitten by highly engorged nymphal

or adult-stage I. scapularis ticks that were estimated to have

been attached for �72 h [68].

In the single-dose doxycycline chemoprophylaxis trial [30],

the number of subjects needed to treat to prevent 1 case of

Lyme disease was 36 (95% CI, 19–244) if everyone with an I.


scapularis tick bite were to have been treated [70]. However,

this number could have been reduced to 12 (95% CI, 6–25) if

prophylaxis were given only to those who removed partially or

fully engorged nymphal ticks [70]. Although the B. burgdorferi

infection rate of adult I. scapularis ticks may be twice that of

nymphal ticks [71], most cases of Lyme disease in humans are

associated with nymphal stage tick bites. This is apparently

caused, at least in part, by the larger size of adult ticks that are

more readily noticed and removed than nymphal I. scapularis

ticks and, therefore, remain attached for a shorter duration of

time [30, 69, 72]. In the single-dose doxycycline chemopro-

phylaxis trial, the estimated median duration of attachment for

adult I. scapularis ticks was 10 h, compared with 30 h for

nymphs ( ) [30].P ! .001

The delay in transmission of B. burgdorferi observed clinically

has also been demonstrated in animal studies. Experimental

studies have demonstrated that B. burgdorferi is rarely trans-

mitted to laboratory animals by nymphal or adult I. scapularis

or nymphal I. pacificus ticks within the first 36 h of attachment

[73–76]. This “grace period” is required for spirochetes in in-

fected ticks to migrate from the tick midgut into the salivary

glands once feeding commences [77]. Although I. scapularis

and I. pacificus ticks that have been attached for !36 h are very

unlikely to transmit B. burgdorferi infection, I. ricinus ticks in

Europe that are infected with B. afzelii appear to transmit in-

fection more rapidly, often within 24 h [78, 79]. Although there

is also a delay in tick transmission of HGA or babesiosis in-

fection in animal systems [80–82], A. phagocytophilum can be

transmitted within the first 24 h of attachment of I. scapularis

ticks [83]. Taken together, the conclusion from the human and

animal studies is that expeditious removal of attached ticks may

be very helpful in prevention of Ixodes species–transmitted

infections.

The option of selectively treating persons with “high-risk”

tick bites to prevent Lyme disease assumes that the species,

stage, and degree of engorgement of the tick can be ascertained.

This requires special expertise. Many different tick species bite

humans, and some “ticks” removed from humans are actually

spiders, scabs, lice, or dirt and, thus, pose no risk of Lyme

disease [68, 84]. Nevertheless, health care practitioners can be

taught to identify ticks (figure 1) and to estimate the degree

of engorgement for use as a marker of the duration of feeding

in a clinical setting (figure 2A and 2B) [85]. Independent as-

sessment by the health care practitioner is necessary because

in areas where exposure to ticks is frequent, the patient’s own

estimate of the duration of attachment is unreliable and usually

is shorter than the actual duration of attachment [68, 86].

Methods for determining the B. burgdorferi infection status of

ticks removed from patients are not standardized, and the re-

sults do not necessarily correlate with the risk of infection [68].

Testing of ticks removed from patients for B. burgdorferi is,

therefore, not recommended except in research studies.

Option 3: antimicrobial therapy only for persons who de-

velop erythema migrans or other clinical manifestations of

Lyme disease or other tick-transmitted infections. The great

majority of persons with B. burgdorferi infection present with

erythema migrans [23, 87–89]. Because primary erythema mig-

rans lesions occur at the site of a tick bite [90–93], a person

who removes a tick should be specifically directed to search for

and seek care for a skin lesion that subsequently develops at

that location. The prognosis for patients who are treated for

erythema migrans is excellent (see Early Lyme Disease, below).

HGA, as well as babesiosis in areas of endemicity, should be

included in the differential diagnosis of patients who develop

fever or clinical illness after an Ixodes tick bite [94–96].

Option 4: antimicrobial therapy for all persons who sero-

convert from a negative to a positive test result for serum

antibodies against B. burgdorferi when acute and follow-up

serum samples are tested simultaneously. To implement this

option, acute and follow-up blood specimens need to be tested

for antibodies in paired samples. The value of acute-phase and

convalescent-phase serologic testing for identifying infection

with B. burgdorferi following a tick bite, however, has not been

demonstrated. There were no asymptomatic seroconversions

after tick bites among untreated subjects in any of the United

States chemoprophylaxis trials [30–33]. Furthermore, no ob-

jective extracutaneous manifestation of Lyme disease developed

in any of the patients in the 3 studies in which patients were

observed for 6 months to 3 years [31–33]. The single-dose

doxycycline chemoprophylaxis trial had a 6-week follow-up

period and was not designed to detect long-term outcomes

[30]. In that study, nonspecific “viral-type” illnesses (i.e., with-

out erythema migrans) were no more frequent in antibiotic-

treated subjects than in untreated subjects, consistent with the

probability that most of these illnesses were unrelated to B.

burgdorferi infection. Although asymptomatic seroconversion

was reported to have occurred rarely in subjects enrolled in a

Lyme vaccine trial [97], mild illnesses or erythema migrans skin

lesions could have gone unnoticed or unreported, because vol-

unteers were only examined if they reported symptoms. Se-

rologic assays for Lyme disease thus far evaluated [98–103] are

of limited use in screening persons lacking objective manifes-

tations of Lyme disease because of their poor specificity (par-

ticularly for IgM reactivity) and cost [98, 99, 101, 102, 104].

Recommendations

1. The best currently available method for preventing in-

fection with B. burgdorferi and other Ixodes species–transmitted

pathogens is to avoid exposure to vector ticks. If exposure to

I. scapularis or I. pacificus ticks is unavoidable, measures rec-

ommended to reduce the risk of infection include the use of


both protective clothing and tick repellents, checking the entire

body for ticks daily, and prompt removal of attached ticks

before transmission of infection can occur (B-III).

2. For prevention of Lyme disease after a recognized tick

bite, routine use of antimicrobial prophylaxis or serologic test-

ing is not recommended (E-III). A single dose of doxycycline

may be offered to adult patients (200 mg dose) and to children

�8 years of age (4 mg/kg, up to a maximum dose of 200 mg)

(B-I) when all of the following circumstances exist: (a) the

attached tick can be reliably identified as an adult or nymphal

I. scapularis tick that is estimated to have been attached for

�36 h on the basis of the degree of engorgement of the tick

with blood or on certainty about the time of exposure to the

tick, (b) prophylaxis can be started within 72 h of the time

that the tick was removed, (c) ecologic information indicates

that the local rate of infection of these ticks with B. burgdorferi

is �20%, and (d) doxycycline is not contraindicated. The time

limit of 72 h is suggested because of the absence of data on

the efficacy of chemoprophylaxis for tick bites following tick

removal after longer time intervals. Infection of �20% of ticks

with B. burgdorferi generally occurs in parts of New England,

in parts of the mid-Atlantic States, and in parts of Minnesota

and Wisconsin, but not in most other locations of the United

States. Whether use of antibiotic prophylaxis after a tick bite

will reduce the incidence of HGA or babesiosis is unknown.

Doxycycline is relatively contraindicated in pregnant women

and children !8 years old. The panel does not believe that

amoxicillin should be substituted for doxycycline in persons

for whom doxycycline is contraindicated because of the absence

of data on an effective short-course regimen for prophylaxis,

the likely need for a multiday regimen (and its associated ad-

verse effects), the excellent efficacy of antibiotic treatment of

Lyme disease if infection were to develop, and the extremely

low risk that a person with a recognized bite will develop a

serious complication of Lyme disease (D-III)

Prophylaxis after I. pacificus bites is generally not necessary

because of low infection rates with B. burgdorferi in almost the

entire region in which this tick is endemic. However, if a higher

infection rate (�20%) were documented in specific local areas,

prophylaxis with single-dose doxycycline would be justified if

the other criteria above are met.

Protective immunity produced by the recombinant OspA

Lyme disease vaccine is not long lasting [105]. A history of

having received the vaccine should not alter the recommen-

dations above, because it is unlikely that previous vaccinations

will still have a protective effect against Lyme disease. Similarly,

it should not be assumed that having had a prior episode of

early Lyme disease will provide protection against developing

B. burgdorferi infection if a bite occurs from another infected

tick.

3. To prescribe antibiotic prophylaxis selectively to pre-

vent Lyme disease, health care practitioners in areas of endem-

icity should learn to identify I. scapularis ticks, including its

stages (figure 1), and to differentiate ticks that are at least

partially engorged with blood (figure 2A and 2B) (A-III). Test-

ing of ticks for tickborne infectious agents is not recommended,

except in research studies (D-II).

4. Health care practitioners, particularly those in areas of

endemicity, should become familiar with the clinical manifes-

tations of Lyme disease, HGA, and babesiosis and recom-

mended practices for diagnosis and treatment (A-III). Persons

who have removed attached ticks from themselves (including

those who have received antibiotic prophylaxis) should be mon-

itored closely for signs and symptoms of tickborne diseases for

up to 30 days and, in particular, for the development of an

expanding skin lesion at the site of the tick bite (erythema

migrans) that may suggest Lyme disease. Persons who develop

a skin lesion or viral infection–like illness within 1 month after

removing an attached tick should promptly seek medical at-

tention to assess the possibility of having acquired a tickborne

infection. HGA, as well as babesiosis in areas of endemicity,

should be included in the differential diagnosis of patients who

develop fever after an Ixodes tick bite (A-II).

EARLY LYME DISEASE


The management options considered included oral antimicro-

bial therapy for patients with a single erythema migrans skin

lesion and oral versus parenteral therapy for patients with clin-

ical evidence of early disseminated infection (i.e., patients pre-

senting with multiple erythema migrans lesions, carditis, cranial

nerve palsy, meningitis, or acute radiculopathy). In view of the

high frequency of travel between North America and Europe,

borrelial lymphocytoma was addressed, despite its rarity in

North America. Its primary etiologic agent is B. afzelii, one of

the exclusively Eurasian species of Lyme borrelia, which are

often referred to as B. burgdorferi sensu lato.

The panel was unable to provide a recommendation on treat-

ment of seropositive patients without erythema migrans be-

lieved to have an acute viral-like illness due to B. burgdorferi

infection because of lack of data, although recommended ther-

apies for the treatment of erythema migrans would likely be

adequate.

Outcomes Evaluated

The panel weighed both the risks and consequences of devel-

oping late complications of Lyme disease and the economic

costs and possible adverse effects of antimicrobial therapy. The

desired outcome is to resolve the symptoms and signs of early

Lyme disease, eradicate B. burgdorferi infection, and prevent

late complications.


Background and Diagnosis of Erythema Migrans

Primary erythema migrans is a round or oval, expanding er-

ythematous skin lesion that develops at the site of deposition

of B. burgdorferi by an Ixodes species tick [90–93, 106–111].

These skin lesions typically become apparent approximately 7–

14 days (range, 3–30 days) after the tick has detached or was

removed and should be at least 5 cm in largest diameter for a

secure diagnosis [112].

An erythematous skin lesion present while an Ixodes tick is

still attached or which has developed within 48 h of detachment

is most likely a tick bite hypersensitivity reaction (i.e., a non-

infectious process), rather than erythema migrans. Tick bite

hypersensitivity reactions are usually !5 cm in largest diameter,

sometimes have an urticarial appearance, and typically begin

to disappear within 24–48 h. In contrast, an early primary

erythema migrans lesion usually increases in size over this time

frame [90, 106]. To differentiate between the 2 processes, it

may be useful to mark the borders of the skin lesion with ink

and then observe for 1–2 days without antibiotic therapy.

When there is 11 erythema migrans skin lesion, the sec-

ondary skin lesions are believed to arise by hematogenous dis-

semination from the site of primary infection [113]. Secondary

erythema migrans skin lesions can be !5 cm in largest diameter,

but like primary lesions, they may expand. In some patients

with multiple erythema migrans skin lesions, the primary lesion

cannot be identified with certainty.

Erythema migrans skin lesions can vary in appearance (figure

3). Some lesions are homogeneously erythematous, whereas

others have prominent central clearing or a distinctive target-

like appearance [65, 91, 110]. On the lower extremities, the

lesion may be partially purpuric. Vesicles or pustules are present

at the center of a primary erythema migrans lesion in ∼5% of

cases [115]. However, unlike contact dermatitis (e.g., from poi-

son ivy), vesicular-appearing erythema migrans lesions are not

associated with significant pruritus. Erythema migrans lesions

are not scaly unless they are long-standing and fading, or topical

corticosteroid creams have been applied. Erythema migrans

lesions often occur at sites (e.g., axilla, popliteal fossa, and

abdomen) that would be highly unusual for community-ac-

quired bacterial cellulitis due to pyogenic bacteria.

Erythema migrans is the only manifestation of Lyme disease

in the United States that is sufficiently distinctive to allow clinical

diagnosis in the absence of laboratory confirmation. In a patient

with a compatible epidemiologic and clinical history, the pre-

ferred means of diagnosis is visual inspection of the skin lesion.

Serologic testing is too insensitive in the acute phase (the first

2 weeks of infection) to be helpful diagnostically [102, 103,

116]. Patients should be treated on the basis of clinical findings.

In a minority of cases for which there may be diagnostic un-

certainty, both acute-phase and convalescent-phase (i.e., 2

weeks after the acute-phase) serum samples should be tested

using the 2-tier testing algorithm recommended by the Centers

for Disease Control and Prevention (CDC) and the Association

of State and Territorial Public Health Laboratory Directors

[117]. Untreated patients who remain seronegative, despite

continuing symptoms for 6–8 weeks, are unlikely to have Lyme

disease, and other potential diagnoses should be actively

pursued.

First-tier testing is most often performed using a polyvalent

ELISA. If the first-tier assay result is positive or equivocal, then

the same serum specimen is retested by separate IgM and IgG

immunoblots. For patients with symptoms in excess of 4 weeks

to be considered seropositive, reactivity must be present on the

IgG immunoblot specifically [117]. To maintain the highest

possible specificity, immunoblot interpretation in this testing

scheme should only be done in qualified laboratories that follow

the CDC-recommended, evidence-based guidelines on im-

munoblot interpretation [117–120]. Alternative recommen-

dations for interpretation of immunoblots have not been rig-

orously validated and are very likely to lead to an inappropriate

diagnosis. Use of single-tier testing with an immunoblot alone

will also result in reduced specificity, because immunoblots are

only semiquantitative, and faint bands are commonly seen in

samples from healthy people without tick exposure and from

patients with illnesses other than Lyme disease [119, 121]. In

interpreting the results of serologic tests, it is also important

to remember that the background rates of seropositivity in areas

with high endemicity may exceed 4% [122]. Therefore, the pres-

ence of seropositivity does not guarantee that a given medical

condition is due to B. burgdorferi infection. Although useful for

documentation of B. burgdorferi infection in research studies,

amplification of B. burgdorferi DNA by PCR or culture of spec-

imens of skin or blood for Borrelia species is not recommended

for diagnosis of erythema migrans in routine clinical care be-

cause of the cumbersome nature and expense of these test

methods [103, 123, 124].

Electrocardiograms are not generally performed for patients

with erythema migrans in the absence of symptoms or signs

suggestive of cardiac disease (see below).

Evidence to support treatment recommendations. In vitro

studies have shown that B. burgdorferi is highly susceptible to

several antimicrobial drug classes, including tetracyclines, most

penicillins, and many second- and third-generation cephalo-

sporins [39, 40, 125–132]. B. burgdorferi is resistant to certain

fluoroquinolones, rifampin, and first-generation cephalospo-

rins [39, 40, 125, 127, 133]. Macrolides may or may not be

active in vitro, depending on the borrelial strain tested and the

assay technique utilized [39, 134–136].

There have been at least 9 randomized, prospective trials

addressing the treatment of early Lyme disease in the United

States [41–43, 137–142]. All studies used erythema migrans as

the disease-defining criterion. Eight studies recruited patients

Figure 3. Illustrative examples of culture-confirmed erythema migrans. A, A single erythema migrans lesion of cm on the abdomen. The8.5 � 5.0lesion is homogeneous in color, except for a prominent central punctum (presumed site of preceding tick bite). B, Patient with 140 erythema migranslesions found. Note the prominent central clearing of the lesions present on the abdomen. Reprinted with permission from [114]. (Copyright 2006,Massachusetts Medical Society. All rights reserved.)


with either localized or disseminated early Lyme disease [41–

43,137–139, 141, 142], whereas 1 study required disseminated

early disease for enrollment [140]. Differing criteria were used

to define treatment failure in the various studies. Most defined

“failure” as the persistence of objective clinical manifestations

despite therapy, whereas others used the persistence of subjec-

tive symptoms.

The etiology of residual patient complaints after treatment

may include an inflammatory response unrelated to active in-

fection or may be due to alternative disease processes. The

possibility that these symptoms may have been related to a tick-

transmitted coinfection was not evaluated in any of the studies.

Importantly, failure rates were not considered in the context

of the high frequency of background complaints present in an

otherwise “healthy” population. Both of these factors have likely

contributed to a misconception by some that recommended

treatment courses are associated with a relatively poor outcome.

This has helped to foster highly speculative theories on how B.

burgdorferi might survive in patients treated with a standard

course of antimicrobial therapy. These issues are discussed in

greater detail below in the section on post–Lyme disease

syndromes.

The first randomized clinical trial on the treatment of ery-

thema migrans compared erythromycin, tetracycline, and pen-

icillin at dosages of 250 mg 4 times per day for 10 days in 112

adult patients [137]. Signs and symptoms after treatment were

considered to be either “minor” (headache, fatigue, suprav-

entricular tachycardia, arthralgias, brief arthritis of !2 weeks

duration, and isolated facial palsy) or “major” (meningitis, me-

ningoencephalitis, carditis, or recurrent attacks of arthritis).

Approximately 15% of patients had a transient intensification

of symptoms during the first 24 h of therapy, consistent with

a Jarisch-Herxheimer–like reaction. These usually mild reac-

tions have only been well-documented at the start of treatment.

There is no evidence that they can last for 124 h or that they

can recur. They have no diagnostic value, and they have not

been shown to be predictive of outcome.

Erythema migrans and its associated symptoms resolved

more rapidly in penicillin- or tetracycline-treated patients, com-

pared with those who were given erythromycin ( ) [137].P ! .05

In addition, treatment with tetracycline or penicillin was as-

sociated with a lower rate of occurrence of “major” manifes-

tations by these criteria, compared with erythromycin. Overall,

“minor” signs and symptoms after treatment occurred in ∼45%

of patients. Extending therapy to 20 days with tetracycline in

a subsequent study by the same authors had no effect on the

frequency of posttreatment symptoms [137]. The results of

these studies supported the findings of a previous open trial

of oral penicillin therapy for early Lyme disease [143]. It could

be concluded from these studies that erythema migrans was

responsive to penicillin and tetracycline, erythromycin was less

effective, and optimal therapy had not been defined.

Subsequent small studies found that doxycycline and amox-

icillin (plus probenecid), the tetracycline and b-lactam prep-

arations most commonly prescribed in current clinical practice

for patients with erythema migrans, were effective therapies,

and each drug regimen had efficacy comparable to the other

[41, 42].

Two of the largest studies of the treatment of erythema mig-

rans in adults compared cefuroxime axetil with doxycycline

[138, 139]. The first was a multicenter study in which 123

patients with erythema migrans were randomized to receive

cefuroxime axetil (500 mg twice per day for 20 days) or dox-

ycycline (100 mg 3 times per day for 20 days). This study

demonstrated comparable efficacy, with satisfactory outcomes

in ∼90% of patients observed for 1 year after treatment [138].

Although 10% of subjects were considered to have experienced

treatment failure on the basis of the presence of continuing

symptoms, most of these patients did not have any objective

clinical finding. Similar results were observed in a second mul-

ticenter study of 232 patients with erythema migrans who were

also randomized to receive 20 days of either cefuroxime or

doxycycline [139]. In a separate randomized trial of 43 children

with erythema migrans, 2 different dosage regimens of cefu-

roxime axetil (20 mg/kg per day or 30 mg/kg per day) were

found to have efficacy comparable to amoxicillin (50 mg/kg

per day) [141].

A multicenter, double-blind, randomized, prospective trial

compared azithromycin (500 mg once per day for 7 days)

with amoxicillin (500 mg 3 times per day for 20 days) for

the treatment of patients with erythema migrans [43]. Amox-

icillin was found to be significantly more effective than azith-

romycin for complete resolution of the acute manifestations

of erythema migrans and for prevention of relapse in a 6-

month period. Of 217 evaluable subjects, only 4% of those

treated with amoxicillin experienced relapse, compared with

16% of those treated with azithromycin ( ). A higherP p .005

symptom score prior to treatment correlated with persistent

symptoms after treatment.

Only 1 study has specifically addressed the treatment of acute

disseminated nonneurologic Lyme disease, which was defined

by the presence of either multiple erythema migrans lesions or

an objective nonneurologic extracutaneous manifestation. Pa-

tients with objective CNS involvement were excluded. This pro-

spective, randomized multicenter trial of 140 patients dem-

onstrated that oral doxycycline (100 mg twice per day for 3

weeks) and intravenous ceftriaxone (2 g per day for 2 weeks)

were equally effective [140]. Importantly, none of the patients

in this study developed a significant late complication.

In most of the controlled trials, patients assigned treatment

with either doxycycline or amoxicillin received ∼3 weeks of


therapy. However, comparable success rates have been reported

in studies in which shorter treatment courses with these an-

tibiotics were used [144]. Duration of antibiotic therapy for

erythema migrans was addressed in a prospective, randomized,

double-blind, placebo-controlled clinical trial of 180 patients

[142]. Patients were randomized into 3 treatment groups: dox-

ycycline (100 mg twice per day by mouth for 10 days); a single

2-g intravenous dose of ceftriaxone, followed by doxycycline

(100 mg twice per day by mouth for 10 days); and doxycycline

(100 mg twice per day by mouth for 20 days). The rate of

complete resolution of signs and symptoms was similar for all

3 treatment groups in both on-study and intention-to-treat

analyses. Despite the potential for B. burgdorferi to disseminate

to the CNS in some patients with erythema migrans [145], the

addition of a single dose of ceftriaxone to a 10-day course of

doxycycline did not improve outcome. The single ceftriaxone

dose, however, was associated with a 4-fold increase in the

frequency of diarrhea ( ) [142].P ! .001

Although none of the prospective studies enrolled pregnant

subjects with Lyme disease, there are no data to suggest that

these patients should be treated differently from other patients

with Lyme disease, except that doxycycline therapy should be

avoided [146].

Several conclusions can be drawn from these trials. Doxy-

cycline, amoxicillin, and cefuroxime axetil are effective for the

treatment of early Lyme disease. Most patients respond

promptly and completely. Some individuals have persistent sub-

jective complaints, despite receiving therapy that otherwise ap-

pears curative. Less than 10% of individuals do not respond

to antibiotic therapy, as evidenced by the presence of objective

clinical manifestations, and rarely is re-treatment required. In

general, patients who are more systemically ill (e.g., febrile with

significant constitutional complaints) at the time of diagnosis

take longer to have a complete response to therapy. Inade-

quately recognized CNS infection at the time of institution of

antibiotic therapy may be the explanation for antibiotic failures

in some circumstances.

The macrolides that have been systematically studied are less

effective than the other antibiotic therapies noted above. Eryth-

romycin [137] and azithromycin [43] have been studied in the

United States, and roxithromycin [147] has been studied in

Europe. Clarithromycin has not been studied in a controlled

trial [148]. Because of these findings, macrolides cannot be

recommended as first-line therapy.

In contrast to the second-generation cephalosporin cefurox-

ime and to certain third-generation cephalosporins (e.g., cef-

triaxone), first-generation cephalosporins, such as cephalexin,

are inactive in vitro against B. burgdorferi and are ineffective

clinically [125, 133].

All antimicrobials effective in early Lyme disease are asso-

ciated with a low frequency of serious adverse effects. Drug-

induced rashes occur with both amoxicillin [43] and cefurox-

ime axetil [138, 139]. Doxycycline may cause photosensitivity

[138, 139], which is a concern, because early Lyme disease

occurs most commonly during the summer months. Individ-

uals treated with doxycycline are advised to avoid exposure to

the sun while receiving therapy. Doxycycline should be taken

with 8 ounces of fluid to reduce the risk of esophageal irritation

and with food to reduce gastrointestinal intolerance. In addi-

tion, doxycycline is relatively contraindicated in children !8

years of age and in women who are pregnant or breast-feeding.

Recommendations

1. Doxycycline (100 mg twice per day), amoxicillin (500

mg 3 times per day), or cefuroxime axetil (500 mg twice per

day) for 14 days (range for doxycycline, 10–21 days; range for

amoxicillin or cefuroxime axetil, 14–21 days) is recommended

for treatment of adult patients with early localized or early

disseminated Lyme disease associated with erythema migrans

in the absence of specific neurologic manifestations (see Early

Neurologic Lyme Disease) or advanced atrioventricular heart

block (tables 2 and 3) (A-I). Ten days of therapy is sufficient

if doxycycline is used; however, given the much shorter half-

life of b-lactam drugs, such as amoxicillin or cefuroxime axetil,

it is unclear whether a 10-day course of these drugs would be

as effective. Therefore, for uniformity, a 14-day course of ther-

apy is recommended for all of the first-line oral agents. Each

of the recommended antimicrobial agents has been shown to

be highly effective in the treatment of erythema migrans and

associated symptoms in prospective studies. Doxycycline has

the advantage of being effective for treatment of HGA (but not

for babesiosis), which may occur simultaneously with early

Lyme disease. Doxycycline is relatively contraindicated during

pregnancy or lactation and in children !8 years of age. For

children, amoxicillin, cefuroxime axetil, or doxycycline (if the

patient is �8 years of age) is recommended (tables 2 and 3)

(A-II).

2. Macrolide antibiotics are not recommended as first-

line therapy for early Lyme disease (E-I). When used, they

should be reserved for patients who are intolerant of, or should

not take, amoxicillin, doxycycline, and cefuroxime axetil (table

3). Patients treated with macrolides should be closely observed

to ensure resolution of the clinical manifestations.

3. First-generation cephalosporins, such as cephalexin, are

ineffective for treatment of Lyme disease and should not be

used (E-II). When erythema migrans cannot be reliably distin-

guished from community-acquired bacterial cellulitis, a rea-

sonable approach is to treat with either cefuroxime axetil or

amoxicillin–clavulanic acid (dosage of amoxicillin–clavulanic

acid for adults, 500 mg 3 times per day; dosage for children,

50 mg/kg per day in 3 divided doses [maximum of 500 mg per


Table 2. Recommended antimicrobial regimens for treatment of patients with Lyme disease.

Drug Dosage for adults Dosage for children

Preferred oral regimensAmoxicillin 500 mg 3 times per daya 50 mg/kg per day in 3 divided doses

(maximum, 500 mg per dose)a

Doxycycline 100 mg twice per dayb Not recommended for children aged !8 yearsFor children aged �8 years, 4 mg/kg per day

in 2 divided doses (maximum, 100 mg perdose)

Cefuroxime axetil 500 mg twice per day 30 mg/kg per day in 2 divided doses(maximum, 500 mg per dose)

Alternative oral regimensSelected macrolidesc For recommended dosing regimens,

see footnote d in table 3For recommended dosing regimens,

see footnote in table 3Preferred parenteral regimen

Ceftriaxone 2 g intravenously once per day 50–75 mg/kg intravenously per day in a singledose (maximum, 2 g)

Alternative parenteral regimensCefotaxime 2 g intravenously every 8 hd 150–200 mg/kg per day intravenously in 3–4

divided doses (maximum, 6 g per day)d

Penicillin G 18–24 million U per day intravenously,divided every 4 hd

200,000–400,000 U/kg per day dividedevery 4 hd (not to exceed 18–24 million Uper day)

a Although a higher dosage given twice per day might be equally as effective, in view of the absence of data on efficacy, twice-daily administration is notrecommended.

b Tetracyclines are relatively contraindicated in pregnant or lactating women and in children !8 years of age.c Because of their lower efficacy, macrolides are reserved for patients who are unable to take or who are intolerant of tetracyclines, penicillins, andcephalosporins.d Dosage should be reduced for patients with impaired renal function.

dose]), because these antimicrobials are generally effective

against both types of infection (A-III).

Ceftriaxone, while effective, is not superior to oral agents

and is more likely than the recommended orally administered

antimicrobials to cause serious adverse effects. Therefore, cef-

triaxone is not recommended for treatment of patients with

early Lyme disease in the absence of neurologic involvement

or advanced atrioventricular heart block (E-I).

4. Pregnant or lactating patients may be treated in a fash-

ion identical to nonpregnant patients with the same disease

manifestation, except that doxycycline should be avoided (B-

III).

5. Because of a lack of biologic plausibility, lack of ef-

ficacy, absence of supporting data, or the potential for harm

to the patient, the following are not recommended for treat-

ment of patients with any manifestation of Lyme disease: first-

generation cephalosporins, fluoroquinolones, carbapenems,

vancomycin, metronidazole, tinidazole, amantadine, ketoli-

des, isoniazid, trimethoprim-sulfamethoxazole, fluconazole,

benzathine penicillin G, combinations of antimicrobials,

pulsed-dosing (i.e., dosing on some days but not others),

long-term antibiotic therapy, anti-Bartonella therapies, hy-

perbaric oxygen, ozone, fever therapy, intravenous immu-

noglobulin, cholestyramine, intravenous hydrogen peroxide,

specific nutritional supplements, and others (see table 4) (E-

III).

6. Coinfection with B. microti or A. phagocytophilum or

both may occur in patients with early Lyme disease (usually in

patients with erythema migrans) in geographic areas where

these pathogens are endemic (see the sections below on post-

Lyme disease syndromes, HGA, and babesiosis). Coinfection

should be considered in patients who present with more severe

initial symptoms than are commonly observed with Lyme dis-

ease alone, especially in those who have high-grade fever for

148 h, despite antibiotic therapy appropriate for Lyme disease

or who have unexplained leukopenia, thrombocytopenia, or

anemia (A-III). Coinfection might also be considered in pa-

tients who have resolved their erythema migrans skin lesion

but have had no improvement or worsening of viral infection–

like symptoms (B-III).

Background and Diagnosis of Early Neurologic Lyme Disease

Manifestations of acute peripheral nervous system involvement

in Lyme disease include radiculopathy, cranial neuropathy, and

mononeuropathy multiplex (multifocal involvement of ana-

tomically unrelated nerves) [107–109, 111, 149–151]. CNS in-

volvement includes lymphocytic meningitis and, rarely, en-

cephalomyelitis (parenchymal inflammation of brain and/or

spinal cord, with focal abnormalities evident on neurologic


Table 3. Recommended therapy for patients with Lyme disease.

Indication TreatmentDuration,

days (range)

Tick bite in the United States Doxycycline, 200 mg in a single dosea,b; (4 mg/kg in children �8 yearsof age) and/or observation

…

Erythema migrans Oral regimenc,d 14 (14–21)e

Early neurologic diseaseMeningitis or radiculopathy Parenteral regimenc,f 14 (10–28)Cranial nerve palsya,g Oral regimenc 14 (14–21)

Cardiac disease Oral regimena,c,h or parenteral regimena,c,h 14 (14–21)Borrelial lymphocytoma Oral regimenc,d 14 (14–21)Late disease

Arthritis without neurologic disease Oral regimenc 28Recurrent arthritis after oral regimen Oral regimena,c

or parenteral regimena,c28

14 (14–28)Antibiotic-refractory arthritisi Symptomatic therapyj …Central or peripheral nervous system disease Parenteral regimenc 14 (14–28)Acrodermatitis chronica atrophicans Oral regimenc 21 (14–28)

Post–Lyme disease syndrome Consider and evaluate other potential causes of symptoms;if none is found, then administer symptomatic therapya

…

NOTE. Regardless of the clinical manifestation of Lyme disease, complete response to treatment may be delayed beyond the treatment duration. Relapsemay occur with any of these regimens; patients with objective signs of relapse may need a second course of treatment.

a See text.b A single dose of doxycycline may be offered to adult patients and to children �8 years of age when all of the following circumstances exist: (1) the

attached tick can be reliably identified as an adult or nymphal Ixodes scapularis tick that is estimated to have been attached for �36 h on the basis of thedegree of engorgement of the tick with blood or of certainty about the time of exposure to the tick, (2) prophylaxis can be started within 72 h after the timethat the tick was removed, (3) ecologic information indicates that the local rate of infection of these ticks with Borrelia burgdorferi is �20%, and (d) doxycyclineis not contraindicated. For patients who do not fulfill these criteria, observation is recommended.

c See table 2.d For adult patients intolerant of amoxicillin, doxycycline, and cefuroxime axetil, azithromycin (500 mg orally per day for 7–10 days), clarithromycin (500 mg

orally twice per day for 14–21 days, if the patient is not pregnant), or erythromycin (500 mg orally 4 times per day for 14–21 days) may be given. Therecommended dosages of these agents for children are as follows: azithromycin, 10 mg/kg per day (maximum of 500 mg per day); clarithromycin, 7.5 mg/kgtwice per day (maximum of 500 mg per dose); and erythromycin, 12.5 mg/kg 4 times per day (maximum of 500 mg per dose). Patients treated with macrolidesshould be closely observed to ensure resolution of the clinical manifestations.

e Ten days of therapy is effective if doxycycline is used; the efficacy of 10-day regimens with the other first-line agents is unknown.f For nonpregnant adult patients intolerant of b-lactam agents, doxycycline (200–400 mg/day orally [or intravenously, if the patient is unable to take oral

medications]) in 2 divided doses may be adequate. For children �8 years of age, the dosage of doxycycline for this indication is 4–8 mg/kg per day in 2 divideddoses (maximum daily dosage of 200–400 mg).

g See text. Patients without clinical evidence of meningitis may be treated with an oral regimen. Parenteral antibiotic therapy is recommended for patientswith both clinical and laboratory evidence of coexistent meningitis. Most of the experience in the use of oral antibiotic therapy is for patients with seventhcranial nerve palsy. Whether oral therapy would be as effective for patients with other cranial neuropathies is unknown. The decision between oral and parenteralantimicrobial therapy for patients with other cranial neuropathies should be individualized.

h A parenteral antibiotic regimen is recommended at the start of therapy for patients who have been hospitalized for cardiac monitoring; an oral regimenmay be substituted to complete a course of therapy or to treat ambulatory patients. A temporary pacemaker may be required for patients with advanced heartblock.

i Antibiotic-refractory Lyme arthritis is operationally defined as persistent synovitis for at least 2 months after completion of a course of intravenous ceftriaxone(or after completion of two 4-week courses of an oral antibiotic regimen for patients who are unable to tolerate cephalosporins); in addition, PCR of synovialfluid specimens (and synovial tissue specimens, if available) is negative for B. burgdorferi nucleic acids.

j Symptomatic therapy might consist of nonsteroidal anti-inflammatory agents, intra-articular injections of corticosteroids, or other medications; expertconsultation with a rheumatologist is recommended. If persistent synovitis is associated with significant pain or if it limits function, arthroscopic synovectomycan reduce the period of joint inflammation.

examination and imaging studies) [107–109, 111, 149–152].

Encephalomyelitis will be discussed in the section on late ner-

vous system Lyme disease.

Although, in the 1980s, early neurologic Lyme disease was

reported to occur in approximately 10%–15% of untreated

patients with Lyme disease in the United States [107, 153, 154],

the frequency of this manifestation is less in recent series [23,

26, 87–89], possibly because of bias of ascertainment in early

studies or improved recognition and treatment of patients with

erythema migrans. In the United States, cranial neuropathy is

the most common manifestation of early neurologic Lyme dis-

ease [4]. Seventh nerve palsy is the most common of the cranial

neuropathies, and bilateral involvement may occur [155, 156].

In areas where Lyme disease is endemic, ∼1 in 4 patients who

present with seventh nerve palsy in nonwinter months can be

shown to have Lyme disease [157]. Seventh nerve palsy due to

Lyme disease can develop in patients who have no recollection

of an erythema migrans lesion or of a tick bite.


Table 4. Selected antimicrobials, drug regimens, or other mo-dalities not recommended for the treatment of Lyme disease.

Doses of antimicrobials far in excess of those provided in tables 2and 3

Multiple, repeated courses of antimicrobials for the same episodeof Lyme disease or a duration of antimicrobial therapy prolongedfar in excess of that shown in table 3

Combination antimicrobial therapyPulsed-dosing (i.e., antibiotic therapy on some days but not on

other days)First-generation cephalosporins, benzathine penicillin G, fluoroquin-

olones, carbapenems, vancomycin, metronidazole, tinidazole, tri-methoprim-sulfamethoxazole, amantadine, ketolides, isoniazid,or fluconazole

Empirical antibabesiosis therapy in the absence of documentationof active babesiosis

Anti-Bartonella therapiesHyperbaric oxygen therapyFever therapy (with or without malaria induction)Intravenous immunoglobulinOzoneCholestyramineIntravenous hydrogen peroxideVitamins or nutritional managementsMagnesium or bismuth injections

Two case-control studies of pediatric patients in the United

States systematically compared selected clinical and laboratory

features of Lyme meningitis with viral meningitis [158, 159].

In these studies, patients with Lyme meningitis were less likely

to be febrile [158] but were more likely to have been ill for a

longer duration of time (median duration, 17 days), compared

with patients with viral meningitis (median duration of head-

ache, 2 days) [159]. The presence of erythema migrans, cranial

nerve palsy, or papilledema was helpful in differentiating the 2

entities; �1 of these 3 physical findings was observed in ∼90%

of patients with Lyme meningitis but in none of the patients

with viral meningitis [158, 159]. In contrast to children, how-

ever, papilledema appears to be uncommon in adults with Lyme

meningitis [160, 161]. The proportion of polymorphonuclear

leukocytes in the CSF of patients with Lyme meningitis is typ-

ically !10% and is significantly lower than that observed in

viral meningitis [158, 159].

The vast majority of patients with early neurologic Lyme

disease are seropositive [157, 162–164]. Patients should have a

total body skin examination to look for a concurrent erythema

migrans lesion and should be questioned to determine whether

one had been present within the preceding 1–2 months. For

the small proportion of patients who have neurologic Lyme

disease but are found to be seronegative by 2-tier testing, a

convalescent-phase serum sample obtained ∼2 weeks after the

acute-phase sample will usually yield positive results.

Another diagnostic test that may be helpful in selected cases

is a test for the presence of intrathecal production of antibody

to B. burgdorferi [103, 152, 165, 166]. Tests to determine specific

intrathecal production of antibody are required, because there

may be passive transfer to the CSF of serum antibody to B.

burgdorferi. Amplification of B. burgdorferi DNA in CSF using

PCR by a laboratory with excellent quality control can also be

useful [103, 124, 167], but few laboratories are capable of ac-

curately performing this test. In the absence of erythema mig-

rans, neurologic manifestations are too nonspecific to warrant

a purely clinical diagnosis; laboratory support for the diagnosis

is required.

Evidence to support treatment recommendations.

Available evidence regarding treatment of acute neurologic

Lyme disease in the United States is derived from small case

series [168]. Patients with Lyme meningitis or acute radicu-

lopathy respond to intravenous penicillin [169], although cef-

triaxone is more widely used for this indication because of its

convenient once-daily dosing [170]. European trials have found

that cefotaxime or ceftriaxone is as effective as intravenous

penicillin [171, 172] and that cefotaxime is as effective as cef-

triaxone [173]. Although experience with the use of oral dox-

ycycline for the treatment of meningitis due to Lyme disease

is limited in the United States, this drug, administered orally

or intravenously, has been used successfully in Europe in adults

and in children �8 years of age [174–179]. These studies, how-

ever, have included few patients with encephalomyelitis [178].

In one prospective, open-label, randomized trial from Europe

[176], patients with neuroborreliosis were treated for 14 days

with either oral doxycycline (200 mg per day; ) or in-n p 31

travenous penicillin (∼20 million U per day; ). No sig-n p 23

nificant differences were found in clinical outcome or post-

treatment CSF test results between the study groups. In another

prospective, open-label, nonrandomized trial from Europe, the

rate of improvement in clinical outcome or in CSF cell counts

was similar for adult patients treated for 10–14 days with either

ceftriaxone (2 g intravenously once per day) ( ) or dox-n p 29

ycycline (200 mg orally twice per day) ( ) [179]. Al-n p 36

though duration of therapy has not been systematically com-

pared in studies of acute neurologic Lyme disease, it is

noteworthy that 10–14 days of antibiotic therapy has been as-

sociated with highly favorable outcomes in both adults [171,

176, 179, 180] and children [178].

Cranial nerve palsy has been treated satisfactorily with oral

antibiotics [107, 155, 175]. One study suggested that the fre-

quency and rate of recovery of seventh nerve palsy in patients

treated with antibiotics appear to be the same as in untreated

patients or in patients treated with corticosteroids, with or

without concomitant antibiotic therapy [155]. In a study con-

ducted in Europe, the authors concluded that oral doxycycline

was effective for treatment of Lyme disease–associated seventh

nerve palsy in patients with CSF pleocytosis [175]. Although


seventh nerve palsy usually resolves with or without antibiotic

treatment, untreated patients may be at especially high risk for

development of Lyme arthritis, which was observed in 14

(87.5%) of 16 patients, according to one report [181]. There-

fore, all patients with cranial nerve palsy in association with

Lyme disease should receive antibiotic therapy, not primarily

for the purpose of expediting recovery from the paralysis, which

will usually resolve within a few weeks regardless of whether

antimicrobial therapy is given, but rather to prevent later com-

plications [181].

Recommendations

1. For adult patients with early Lyme disease and the acute

neurologic manifestations of meningitis or radiculopathy, the

use of ceftriaxone (2 g once per day intravenously for 14 days;

range, 10–28 days) is recommended (tables 2 and 3) (B-I).

Parenteral therapy with cefotaxime or penicillin G may be a

satisfactory alternative (B-I). For patients who are intolerant

of b-lactam antibiotics, increasing evidence indicates that dox-

ycycline (200–400 mg per day in 2 divided doses orally for 10–

28 days) may be adequate (B-I). Doxycycline is well absorbed

orally; thus, intravenous administration should only rarely be

needed.

For children, ceftriaxone (B-I) or cefotaxime (B-II) admin-

istered parenterally is recommended (tables 2 and 3); intra-

venous penicillin G is an alternative (B-I). Children �8 years

of age have also been successfully treated with oral doxycycline

at a dosage of 4–8 mg/kg per day in 2 divided doses (maximum,

100–200 mg per dose) (B-II).

The presence of either papilledema or sixth cranial nerve

palsy may indicate the presence of increased intracranial pres-

sure. Although elevated intracranial pressure typically responds

to systemic antibiotic therapy, other measures to lower pressure,

such as serial lumbar punctures and use of corticosteroids or

acetazolamide, may be considered in individual cases [160,

161]. CSF shunting was thought to be necessary in one patient

to control increased intracranial pressure that appeared to be

causing or contributing to loss of vision [160].

2. Although antibiotic treatment may not hasten the res-

olution of seventh cranial nerve palsy associated with B. burg-

dorferi infection, antibiotics should be given to prevent further

sequelae (A-II). Cranial nerve palsies in patients with Lyme

disease are often associated with a lymphocytic CSF pleocytosis,

with or without symptoms of meningitis. Panel members dif-

fered in their approach to the neurologic evaluation of patients

with seventh cranial nerve palsy. Some perform a CSF exam-

ination on all patients with Lyme disease–associated seventh

cranial nerve palsy. Others do not, because of the good clinical

response with orally administered antibiotics (even in the pres-

ence of a CSF pleocytosis) and the absence of evidence of

recurrent CNS disease in these patients. There was agreement

that lumbar puncture is indicated for those in whom there is

strong clinical suspicion of CNS involvement (e.g., severe or

prolonged headache or nuchal rigidity). Patients with normal

CSF examinations and those in whom CSF examination is

deemed unnecessary because of lack of clinical signs of men-

ingitis may be treated with a 14-day course (range, 14–21 days)

of the same antibiotics used for patients with erythema migrans

(B-III). Those with both clinical and laboratory evidence of

CNS involvement should be treated with regimens effective

against meningitis, as in recommendation number 1 above (ta-

bles 2 and 3) (B-III).

Background and Diagnosis of Cardiac Manifestationsof Lyme Disease

Patients with symptomatic cardiac involvement associated with

Lyme disease usually present with the acute onset of varying

degrees of intermittent atrioventricular heart block, sometimes

in association with clinical evidence of myopericarditis [182–

188]. Electrophysiologic studies have usually demonstrated

block occurring above the bundle of His, often involving the

atrioventricular node, but heart block may occur at multiple

levels [182–184]. Severe or fulminant congestive heart failure

or development of valvular heart disease is not associated with

Lyme disease [183]. In the United States, there is no convincing

evidence that Lyme disease is a cause of chronic cardiomy-

opathy [189, 190].

Although Lyme carditis had earlier been reported to occur

in 4%–10% of untreated United States patients with Lyme dis-

ease, the frequency of this manifestation is much lower in more

recent series [183, 191]. This change, like that observed for

acute neurologic manifestations, could possibly be the result of

a bias of ascertainment in early studies or improved recognition

and treatment of patients with erythema migrans. No evidence

of carditis was found among 233 case patients diagnosed with

definite Lyme disease in 2 prospective studies on the evaluation

of a recombinant OspA vaccine [23, 89]. Because carditis usu-

ally occurs within 2 months after onset of infection, erythema

migrans [182, 186, 187] or neurologic Lyme disease [182, 187]

may occur concomitantly or in close proximity, which may be

helpful diagnostically. In the absence of concomitant erythema

migrans (present in up to 85% of cases [186]), the clinical

manifestations of Lyme carditis are too nonspecific to warrant

a purely clinical diagnosis. Under these circumstances, support

for the diagnosis requires the presence of B. burgdorferi anti-

body in acute- or convalescent-phase (2–4 weeks after the acute

phase) serum specimens. The vast majority of patients with

cardiac manifestations of Lyme disease are seropositive at the

time of presentation [183, 192].

Because of the potential for life-threatening complications,

hospitalization and continuous monitoring are advisable for

symptomatic patients (e.g., those with syncope, dyspnea, or

chest pain). These interventions are also suggested for patients


with second- or third-degree atrioventricular block, as well as

for those with first degree heart block when the PR interval is

prolonged to �30 milliseconds, because the degree of block

may fluctuate and worsen very rapidly in such patients [182].

Evidence to support treatment recommendations. No

studies have specifically addressed the treatment of Lyme car-

ditis. Although there is no evidence that antibiotic therapy has-

tens the resolution of cardiac abnormalities, antibiotic therapy

is recommended for patients with Lyme carditis with this pur-

pose in mind and to prevent later manifestations of Lyme dis-

ease [183]. There are no comparative treatment trials in carditis,

and there is no evidence to suggest that parenteral antibiotic

therapy is more effective than oral antibiotic therapy. A tem-

porary pacemaker may be required in patients with advanced

heart block for the duration of the block [183, 187]. Complete

heart block generally resolves within 1 week, and lesser con-

duction disturbances resolve within 6 weeks [182, 186, 187].

Recommendations

1. Patients with atrioventricular heart block and/or my-

opericarditis associated with early Lyme disease may be treated

with either oral or parenteral antibiotic therapy for 14 days

(range, 14–21 days). Hospitalization and continuous monitor-

ing are advisable for symptomatic patients, such as those with

syncope, dyspnea, or chest pain. It is also recommended for

patients with second- or third-degree atrioventricular block, as

well as for those with first-degree heart block when the PR

interval is prolonged to �30 milliseconds, because the degree

of block may fluctuate and worsen very rapidly in such patients.

For hospitalized patients, a parenteral antibiotic, such as cef-

triaxone (see recommendation above for treatment of men-

ingitis) (table 2), is recommended as initial treatment, although

there are no clinical trials to support this recommendation (B-

III). For patients with advanced heart block, a temporary pace-

maker may be required; expert consultation with a cardiologist

is recommended. The pacemaker may be discontinued when

the advanced heart block has resolved. An oral antibiotic reg-

imen should be used for completion of therapy and for out-

patients, as is used for patients with erythema migrans without

carditis (tables 2 and 3) (B-III).

Background and Diagnosis of Borrelial Lymphocytoma

Borrelial lymphocytoma is a rare cutaneous manifestation of

Lyme disease in Europe, which presents as a solitary bluish-red

swelling with a diameter of up to a few centimeters [109, 193–

196]. The most common site of borrelial lymphocytoma is the

ear lobe in children and the breast, on or near the nipple, in

adults. Mild, localized discomfort often accompanies the skin

lesion. Borrelial lymphocytoma is characterized histologically

by a dense polyclonal and predominantly B lymphocytic infil-

tration of the cutis and subcutis, frequently with germinal cen-

ter formation [109, 197]. Borrelial lymphocytoma may be the

only sign of Lyme disease or merely one of several manifes-

tations during the course of the illness. It often appears near

the site of a prior tick bite and frequently arises in the vicinity

of a previous or concurrent erythema migrans lesion, but com-

pared with erythema migrans, it usually emerges later and lasts

longer (untreated borrelial lymphocytoma may persist for many

months or even for 11 year) [109, 193, 194, 197].

In general, diagnosing borrelial lymphocytoma is more chal-

lenging than diagnosing erythema migrans, largely because of

lack of awareness of this rare condition. It is easiest when the

location of the lesion is on the ear lobe, much more difficult

if on the breast, and even more difficult if in other (atypical)

locations [194]. The diagnosis is supported by the history or

presence of erythema migrans, and the majority of patients are

seropositive [109, 193, 195, 198, 199]. Histological examination

is recommended in patients with suspected borrelial lympho-

cytoma at a location other than the ear lobe. Borrelial lym-

phocytoma on the breast must be differentiated from malig-

nancy [109].

Evidence to support treatment recommendations. There

are no prospective, randomized studies on the treatment of

borrelial lymphocytoma. When borrelial lymphocytoma is the

only manifestation of Lyme disease or is associated with ery-

thema migrans, it is usually treated with antimicrobial regimens

that are used for therapy of erythema migrans (tables 2 and

3). Such a therapeutic approach resulted in complete recovery

within 1–12 weeks (median, 2 weeks) in a group of 52 adults

and children [200]. Two (4%) of these patients, however, de-

veloped an objective extracutaneous manifestation of Lyme dis-

ease after treatment; both were among the 19 patients in this

study who had been treated with phenoxymethylpenicillin. An-

other study revealed similar findings [194]. Among 63 adult

patients with borrelial lymphocytoma treated with oral anti-

biotics for 14 days, the lesion disappeared within 4 weeks after

the start of therapy in 49 patients (78%) and within 6 weeks

in 59 patients (94%) [194]. Both reports indicated that reso-

lution of the lesion was faster in patients with a shorter duration

of borrelial lymphocytoma prior to institution of antimicrobial

therapy [194, 200].

Recommendations

1. Available data indicate that borrelial lymphocytoma

may be treated with the same treatment regimens used to treat

patients with erythema migrans (see tables 2 and 3) (B-II).

LATE LYME DISEASE


The panel considered various oral and parenteral antimicrobial

regimens for treatment of the late manifestations of Lyme dis-


ease. Late manifestations include arthritis, encephalopathy, en-

cephalomyelitis, and peripheral neuropathy. In view of the high

frequency of travel between North America and Europe, ac-

rodermatitis chronica atrophicans was addressed, despite its

rarity in North America. Dermatologic manifestations that are

even less common or less–well substantiated were not consid-

ered [201]. The panel did not make recommendations on ker-

atitis and other possible ocular manifestations of Lyme disease

because of the lack of evaluable data on ophthalmologic com-

plications, which are very rare [160, 202]. Because of lack of

data, the panel was also unable to provide a recommendation

on treatment of asymptomatic individuals who are seropositive

for antibodies to B. burgdorferi but have no history of Lyme

disease.

The response to treatment of late manifestations may be slow,

and weeks to months may be required for improvement or

resolution of symptoms after treatment. However, appropriate

antibiotic treatment leads to recovery in most patients.

Outcomes Evaluated

The panel compared the risks and consequences of ineffective

treatment of late Lyme disease with the problems resulting from

adverse effects of antimicrobial therapies. The desired outcome

is to treat effectively the late complications of Lyme disease

while minimizing the adverse effects from antibiotic therapy

and economic costs. The effects of the different treatment strat-

egies on quality of life were considered.

Background and Diagnosis of Rheumatologic Manifestationsof Lyme Disease

Although Lyme arthritis was reported to occur in 60% of un-

treated patients in the United States with Lyme disease nearly

20 years ago [153], the frequency of this manifestation has been

�10% in recent series [23, 26, 87–89], probably because of

improved recognition and earlier treatment of patients with

early Lyme disease. However, the frequency of arthritis among

the 40,792 cases of Lyme disease reported to the CDC for the

years 2001–2002 was at least 24.8% [4]. Possible explanations

for the higher proportion of arthritis cases in national reporting

include reporting bias favoring the tabulation of seropositive

Lyme disease cases, confusion between arthritis and arthralgia

by the treating health care provider [203], and inaccuracy of

Lyme disease diagnosis [203]. In addition, surveillance report

forms differ by state, and reported seropositivity in support of

a diagnosis of Lyme arthritis is not necessarily based on 2-tier

testing [112].

Lyme arthritis is a monoarticular or oligoarticular form of

arthritis that typically involves the knee [107, 111, 153, 204–

206]. However, other large joints or the temporomandibular

joint may be involved. Large knee effusions that are out of

proportion to the pain are typical. A Baker’s cyst may develop

and may rupture. Lyme arthritis is often intermittent in nature

if untreated, with episodes of joint inflammation spontaneously

resolving after a few weeks to a few months. Persistent swelling

of the same joint for �12 months would be an unusual pre-

senting manifestation of Lyme arthritis.

Synovial fluid usually shows mild-to-moderate inflamma-

tion, with a median leukocyte count of 24,250 leukocytes/mm3

in one study [204]; typically, there is a predominance of gran-

ulocytes [204, 206]. In the vast majority of patients, the clinical

manifestations are too nonspecific to warrant a purely clinical

diagnosis of Lyme arthritis. Confirmation of the diagnosis re-

quires serologic testing. All patients should be determined to

be seropositive by 2-tier testing that includes an ELISA and

IgG immunoblot [162, 206]. In a seropositive patient, a positive

PCR test result on a synovial fluid specimen adds increased

diagnostic certainty [206, 207]. Positive PCR results for a joint

fluid specimen from a seronegative patient, however, should

be regarded with skepticism [103].

Background and Diagnosis of Late Neurologic Lyme Disease

Late neurologic Lyme disease may present as encephalomyelitis,

peripheral neuropathy, or encephalopathy [149–152, 208–212].

Because most patients with Lyme disease are now diagnosed

and treated early in the course of infection, these more indolent

forms of neurologic Lyme disease are quite rare. Encephalo-

myelitis is a unifocal or multifocal inflammatory CNS disease

[152, 213]. Collectively, only 1 patient with encephalomyelitis

has been diagnosed over the past 5 years by panel members

(G.P.W., J.J.H., R.B.N., R.J.D., A.C.S., E.D.S., M.S.K., P.J.K.,

J.S.B., and L.B.), in spite of both community-based and referral

clinical practices. This severe neurologic manifestation of Lyme

disease has been diagnosed primarily in Europe.

In untreated patients, encephalomyelitis has been mono-

phasic and slowly progressive, principally involving white mat-

ter. Two-tier (ELISA and IgG immunoblot) seropositivity with

serum samples and evidence of intrathecal antibody production

to B. burgdorferi are expected [149, 162, 213]. Intrathecal an-

tibody production, however, may persist for years following

successful treatment, so this parameter does not provide a use-

ful marker of disease activity [214]. CSF examination typically

shows a lymphocytic pleocytosis, a moderately elevated protein

level, and a normal glucose level [149, 213]. Sensitivity of PCR

for detection of B. burgdorferi DNA in the CSF of such patients

is extremely low. MRI of the affected part of the neuraxis can

demonstrate areas of inflammation, typically with increased

signal on T2 and FLAIR imaging and enhancement following

contrast administration [149, 215].

Lyme encephalomyelitis may be confused clinically with a

first episode of relapsing-remitting multiple sclerosis or primary

progressive multiple sclerosis, but appropriate CSF and serum


studies for B. burgdorferi–specific antibody should differentiate

between these entities in most instances [216–218].

Late neurologic Lyme disease–associated peripheral neurop-

athy typically presents as a mild, diffuse, “stocking glove” pro-

cess. Only 9 such patients have been diagnosed by panel mem-

bers (G.P.W., J.J.H., R.B.N., R.J.D., A.C.S., E.D.S., M.S.K., P.J.K.,

J.S.B., and L.B.) over the past 5 years. Patients typically com-

plain of intermittent limb paresthesias, and some patients com-

plain of radicular pain. The most frequent abnormality found

on neurologic examination is reduced vibratory sensation of

the distal lower extremities. Electrophysiologic studies show

findings consistent with a mild confluent mononeuritis mul-

tiplex [219]. Nerve biopsy reveals small perivascular collections

of lymphocytes, without spirochetes [220, 221]. Serum IgG

antibody to B. burgdorferi detected by the 2-tier approach is

expected in patients with Lyme disease–associated peripheral

neuropathy. The absence of antibody should lead to an alter-

native diagnosis [149]. Because the pathophysiologic process

usually occurs outside the subarachnoid space, CSF findings

are often normal, without evidence of intrathecal antibody pro-

duction to B. burgdorferi.

Lyme disease–associated encephalopathy is an imprecisely

defined clinical entity characterized by mild abnormalities of

memory and cognitive functions that are demonstrable either

by a careful mental status examination or by formal neurop-

sychologic testing [211, 222]. Panel members (G.P.W., J.J.H.,

R.B.N., R.J.D., A.C.S., E.D.S., M.S.K., P.J.K., J.S.B., and L.B.)

have diagnosed only 7 patients over the past 5 years. In the

past, certain patients with this condition had concomitant Lyme

arthritis [211]. In such patients, CSF examination findings were

often normal, and the process may have been related to general

illness rather than CNS infection (i.e., “toxic-metabolic” in or-

igin). Other patients have had evidence of intrathecal antibody

production to B. burgdorferi and/or increased CSF protein lev-

els, with or without a mild CSF pleocytosis [208, 211, 222]. In

these cases, the encephalopathy may actually be a mild form

of encephalomyelitis. Cranial imaging studies may occasionally

demonstrate focal areas of presumed parenchymal inflamma-

tion. Most often, findings are normal or demonstrate only mi-

nor, nonspecific abnormalities; consequently, cranial imaging

plays little if any role in the diagnosis or follow-up of patients

with this entity [223]. In serum, 2-tier IgG seropositivity is

expected [149, 208, 211, 222, 223].

The panel has differentiated between early and late neurol-

ogic Lyme disease in these guidelines, as is customary. There

is little evidence to support a pathophysiological basis for this

distinction, however, and differences may be related more to

the degree of involvement [208, 217, 219].

Evidence to support treatment recommendations. The first

study of antibiotic treatment in patients with Lyme arthritis

was initiated in 1980 [224]. The regimens tested were those

used for the treatment of tertiary syphilis, and the study design

was a double-blind, placebo-controlled trial. Study patients had

intermittent or chronic Lyme arthritis primarily affecting the

knees, and all were subsequently shown to be seropositive for

antibodies to B. burgdorferi. In the first phase of the study, 40

patients were randomized to receive either intramuscular ben-

zathine penicillin G (7.2 million U) or placebo. In the second

phase, 20 patients were treated with intravenous penicillin G

(20 million U per day for 10 days); oral or intramuscular an-

tibiotic treatment had already failed for 6 of these patients. Of

the 20 patients who received intramuscular benzathine peni-

cillin, 7 (35%) had complete resolution of joint involvement

within 1 month of initiation of treatment, compared with none

of 20 patients who were given placebo ( ). Of the 20P ! .02

patients treated with intravenous penicillin G, 11 (55%) had

complete resolution of arthritis soon after treatment. It was

concluded that parenteral penicillin was often effective in the

treatment of Lyme arthritis, but a substantial percentage of

patients did not respond.

Subsequently, a series of studies was begun to test the efficacy

of intravenous ceftriaxone in the treatment of late Lyme disease.

Compared with penicillin, the advantages of ceftriaxone are its

excellent CSF penetration and long serum half-life, which per-

mits once-per-day dosing. In 1987, a case series of 7 patients

with Lyme arthritis or chronic neuroborreliosis, who were re-

fractory to oral or intravenous penicillin therapy, were then

treated with intravenous ceftriaxone (2 or 4 g per day for 2

weeks) [225]. All 5 patients who had arthritis responded to

ceftriaxone therapy, and 5 of the 6 patients with limb pares-

thesias experienced a reduction in their symptoms and had

improvement in nerve conduction studies. In a follow-up study,

23 patients with Lyme arthritis or late neuroborreliosis were

randomly assigned to receive penicillin (20 million U per day

intravenously for 10 days) or ceftriaxone (4 g per day intra-

venously for 14 days) [226]. Of the 13 patients who received

ceftriaxone, none had objective evidence of persistent disease

after treatment, although 3 had mild arthralgias, and 1 com-

plained of fatigue and memory difficulty. In contrast, 5 of the

10 patients who received intravenous penicillin continued to

have fatigue, memory deficit, or recurrent oligoarthritis at 3

months after treatment. Four of these 5 patients had resolution

of their symptoms after re-treatment with ceftriaxone.

In a subsequent study, 31 patients with Lyme arthritis or late

neuroborreliosis were treated with either 2 g or 4 g per day of

ceftriaxone for 2 weeks (the first 17 patients enrolled received

the 4-g dose and the next 14 patients received the 2-g dose)

[226]. Following treatment, 3 of the 31 patients had persistent

encephalopathy, 2 had persistent neuropathy, and 3 had no

improvement in their arthritis. The overall frequency of per-

sistent symptoms among patients was 13%, which was similar

in both dosage groups. Duration of ceftriaxone treatment was


investigated in an open-label, randomized, multicenter study.

In this study, 143 evaluable patients with manifestations of late

Lyme disease (primarily Lyme arthritis) were treated with in-

travenous ceftriaxone (2 g per day for either 2 or 4 weeks)

[227]. In this study, assessment was done at 3-month intervals

for 12 months; primary assessment of outcome was at the time

point of last evaluation. There was no significant difference in

the clinical cure rates between the 2-week and 4-week treatment

groups (76% and 70%, respectively). The most common per-

sistent symptoms were arthralgia, pain, weakness, malaise, and

fatigue. At time of the last evaluation, 5 patients in the 2-week

treatment group had no apparent response to therapy, com-

pared with none in the 4-week group ( ). The later theP p .07

time point of evaluation, the higher the proportion of patients

who were categorized as cured. A greater proportion of patients

in the 4-week treatment group than in the 2-week group had

therapy prematurely discontinued because of adverse events

( ). The principal conclusion of these 2 studies is thatP ! .02

daily parenteral administration of ceftriaxone at a dosage of 2

g per day for 2 weeks is effective in resolving illness in the

majority of patients with late Lyme disease. However, some

patients have persistent symptoms despite receiving ceftriaxone

treatment.

At the same time that studies were being performed to assess

parenteral antibiotic regimens, oral therapy was also found to

be effective in the treatment of patients with Lyme arthritis. In

1983 and 1984, a total of 14 children with Lyme arthritis were

treated orally with either phenoxymethyl penicillin or tetra-

cycline for 10–30 days [228]. Thirteen experienced no further

attacks of arthritis at follow-up 4–24 months after treatment,

while 1 patient’s symptoms did not resolve until after he re-

ceived a 10-day course of intravenous penicillin.

From 1986 through 1991, a total of 48 adult and pediatric

patients with Lyme arthritis were randomly assigned to receive

a 30-day course of doxycycline (100 mg orally twice per day)

or amoxicillin plus probenecid (500 mg of each 4 times per

day) [44]. Eighteen of the 20 evaluable patients treated with

doxycycline and 16 of the 18 evaluable patients who completed

the amoxicillin-probenecid regimen had resolution of arthritis

1–3 months after study entry. However, neuroborreliosis later

developed in 5 patients, 4 of whom received the amoxicillin-

probenecid regimen. The concomitant use of probenecid with

amoxicillin may be inadvisable, because probenecid may impair

penetration of b-lactam antibiotics into brain parenchyma [170,

229]. In retrospect, all 5 patients reported subtle distal pares-

thesias or memory impairment at the time of study entry. It

was concluded that patients with Lyme arthritis can usually be

treated successfully with oral antibiotics, but practitioners must

be aware of subtle neurologic symptoms, which may require

treatment with intravenous b-lactam antibiotics.

In a cost-effectiveness analysis, intravenous therapy was

found to be no more cost-effective than oral therapy for patients

with Lyme arthritis; intravenous therapy was more likely to

result in serious complications and was substantially more ex-

pensive [230]. Thus, the authors concluded that oral antibiotics

are preferred in the initial treatment of Lyme arthritis in the

absence of concomitant neurologic involvement.

Not all patients with Lyme arthritis respond to 2–4-week

courses of oral or intravenous antibiotic therapy. In one treat-

ment trial, 16 patients with Lyme arthritis who had continuous

joint swelling for at least 3 months, despite receiving 4-week

courses of oral antibiotics, did not have resolution of arthritis

when they were subsequently treated with intravenous ceftriax-

one (2 g per day for 2 weeks) either [44]. These 16 patients

were found to have distinctive immunogenetic and immune

markers, including a high frequency of the HLA-DR4 allele and

of antibody reactivity with OspA of the spirochete. More recent

data based on PCR testing of serial joint fluid samples suggest

that arthritis may persist in a small number of patients, despite

apparent eradication of the spirochete (i.e., absence of ampli-

fiable B. burgdorferi DNA by PCR) [205, 207, 231]. In these

patients, it has been postulated that a T cell epitope of OspA

may cross-react with a human protein, leading to an autoim-

mune response as a possible explanation for the persistent joint

inflammation [205, 232]. This form of arthritis is termed “an-

tibiotic-refractory Lyme arthritis” [233]. It can be operationally

defined as persistent synovitis for at least 2 months after com-

pletion of a course of intravenous ceftriaxone (or after com-

pletion of two 4-week courses of an oral antibiotic for patients

unable to tolerate cephalosporins), in conjunction with negative

results of PCR of synovial fluid specimens, and of synovial tissue

specimens if available [231, 234]. Arthroscopic synovectomy

has been used successfully in the treatment of patients with

antibiotic refractory Lyme arthritis. Of 20 patients who un-

derwent this procedure for refractory chronic Lyme arthritis of

the knee, 16 (80%) had resolution of joint inflammation during

the first month after surgery or soon thereafter [235]. The

remaining 4 patients (20%) had persistent or recurrent syno-

vitis. No patient, however, has been documented to have per-

sistent joint inflammation of 15 years’ duration [236]. Anec-

dotally, some patients with antibiotic-refractory arthritis have

appeared to benefit from intraarticular injections of cortico-

steroids, systemic administration of nonsteroidal anti-inflam-

matory agents (NSAIDs), or DMARDs, primarily hydroxy-

chloroquine [206, 237, 238].

Patients with late Lyme disease associated with prominent

neurologic features also respond to antibiotic therapy. In a trial

conducted from 1987 through 1989, a total of 27 adult patients

with Lyme encephalopathy, polyneuropathy, or both were

treated with intravenous ceftriaxone (2 g per day for 2 weeks)

[208]. In addition to clinical signs and symptoms, outcome

measures included CSF analyses and neuropsychological tests


of memory. Response to therapy was usually gradual and did

not begin until several months after treatment. When measured

6 months after treatment, 17 patients (63%) had uncomplicated

improvement, 6 (22%) had improvement but then had relapse,

and 4 (15%) had no change in their condition.

In a subsequent study, the same investigators treated 18 adult

patients with Lyme encephalopathy with intravenous ceftriax-

one (2 g per day for 30 days) [222]. Of the 18 patients, 16 had

abnormal verbal or visual memory scores on neuropsychologic

tests, and 16 had CSF abnormalities, most commonly intra-

thecal antibody production to B. burgdorferi or an elevated total

protein level. As determined 6 months after treatment, 14

(93%) of the 15 patients examined had improvement in symp-

toms; verbal memory scores in the 15 patients were significantly

improved ( ). The total CSF protein values were signif-P ! .01

icantly less in the 10 patients who had follow-up analyses

( ). At 12–24 months, all patients were back to normalP ! .05

or improved (1 of the 18 patients was re-treated after 8

months). It was concluded that Lyme encephalopathy may be

associated with active infection of the nervous system and that

the infection can be treated successfully in most patients with

a 30-day course of intravenous ceftriaxone. Whether a 30-day

course is superior to 14 days of treatment is unclear. Although

the data are much more limited, children with neurocognitive

abnormalities attributed to Lyme disease also appear to improve

after 2–4 weeks of intravenous ceftriaxone [239].

The third-generation cephalosporin cefotaxime has been

tested in Europe and has been found to be effective in the

treatment of late Lyme disease [240]. Although cefotaxime must

be administered 3–4 times per day, compared with once-daily

administration for ceftriaxone, it does not cause the biliary

complications that have been associated with ceftriaxone ther-

apy [241].

Recommendations

1. Lyme arthritis can usually be treated successfully with

antimicrobial agents administered orally (tables 2 and 3). Dox-

ycycline (B-I), amoxicillin (B-I), or cefuroxime axetil (B-III)

for 28 days is recommended for adult patients without clinical

evidence of neurologic disease. For children, amoxicillin (B-I),

cefuroxime axetil (B-III), or doxycycline (if �8 years of age)

(B-I) is recommended (tables 2 and 3). Oral therapy is easier

to administer than intravenous antibiotics, is associated with

fewer serious complications, and is considerably less expensive.

However, it is important to recognize that a small number of

patients treated with oral agents have subsequently manifested

overt neuroborreliosis, which may require intravenous therapy

with a b-lactam antibiotic for successful resolution. Further

controlled trials are needed to compare the safety and efficacy

of oral therapy with intravenous therapy for Lyme arthritis.

Neurologic evaluation that may include lumbar puncture

should be performed for patients in whom there is a clinical

suspicion of neurologic involvement. Adult patients with ar-

thritis plus objective evidence of neurologic disease should re-

ceive parenteral therapy with ceftriaxone (tables 2 and 3) (A-

II). Cefotaxime or penicillin G administered parenterally is an

acceptable alternative (B-II). For children, intravenous ceftriax-

one or intravenous cefotaxime is recommended (B-III); pen-

icillin G administered intravenously is an alternative (B-III)

(tables 2 and 3).

2. Patients who have persistent or recurrent joint swelling

after a recommended course of oral antibiotic therapy should be

re-treated with another 4-week course of oral antibiotics or with

a 2–4-week course of intravenous ceftriaxone (B-III) (tables 2

and 3). A second 4-week course of oral antibiotic therapy is

favored by panel members for the patient whose arthritis has

substantively improved but has not yet completely resolved, re-

serving intravenous antibiotic therapy for those patients whose

arthritis failed to improve at all or worsened. Clinicians should

consider waiting several months before initiating re-treatment

with antimicrobial agents because of the anticipated slow reso-

lution of inflammation after treatment. During this period,

NSAIDs may be used, but intra-articular injections of cortico-

steroids are not recommended (D-III). If patients have no res-

olution of arthritis despite intravenous therapy, and if PCR results

for a sample of synovial fluid (and synovial tissue, if available)

are negative, symptomatic treatment is recommended (B-III).

Symptomatic therapy might consist of NSAIDs, intra-articular

injections of corticosteroids, or DMARDs, such as hydroxychlor-

oquine; expert consultation with a rheumatologist is recom-

mended. If persistent synovitis is associated with significant pain

or limitation of function, arthroscopic synovectomy may reduce

the duration of joint inflammation (B-II).

3. Adult patients with late neurologic disease affecting the

central or peripheral nervous system should be treated with cef-

triaxone (2 g once per day intravenously for 2–4 weeks) (tables

2 and 3) (B-II). Cefotaxime or penicillin G administered intra-

venously is an alternative (B-II). Response to treatment is usually

slow and may be incomplete. Re-treatment is not recommended

unless relapse is shown by reliable objective measures. Ceftriax-

one is also recommended for children with late neurologic Lyme

disease (tables 2 and 3) (B-II). Cefotaxime or penicillin G ad-

ministered intravenously is an alternative (B-III).

Background and Diagnosis of Acrodermatitis ChronicaAtrophicans

Acrodermatitis chronica atrophicans is a late skin manifestation

of Lyme disease that develops insidiously several years after

initial infection (range, 0.5–8 years) [109, 242].

Approximately 20% of patients have a history of a preceding

erythema migrans lesion, usually of the same extremity [242].

Acrodermatitis chronica atrophicans is diagnosed most fre-

quently in women 140 years of age. Although any of the species


Figure 4. Illustrative example of a patient with acrodermatitis chronicaatrophicans. The picture is a generous gift from Dr. Franc Strle (UniversityMedical Center, Ljubljana, Slovenia).

of Lyme Borrelia may cause the lesion, by far the most common

etiologic agent is B. afzelii. Therefore, this manifestation is

much more common in Europe than in the United States [243–

246].

Acrodermatitis chronica atrophicans occurs most often on

the extensor surfaces of the hands and feet, and early lesions

are characterized by a slight bluish-red discoloration and

doughy swelling. Initially unilateral, the lesion may later be-

come bilateral. The lesion enlarges slowly over months to years,

in association with resolution of the edema and development

of skin atrophy (figure 4) (sometimes referred to as “cigarette

paper skin”). Nodules may develop over bony prominences,

such as the elbow or patella [197, 242, 247]. In some patients,

sclerosing lesions develop. Because of atrophy of the skin, the

veins become prominent, which may lead to a misdiagnosis of

venous insufficiency [109, 197, 242]. Approximately two-thirds

of patients have an associated peripheral neuropathy, typically

involving the affected extremity, manifested primarily as local

sensory loss [248, 249].

The diagnosis of acrodermatitis chronica atrophicans is based

on appropriate epidemiology, clinical characteristics, histolog-

ical findings, and IgG seropositivity. Histopathology shows a

pronounced lymphoplasmacellular infiltration of the skin and

sometimes also of the subcutis, with or without atrophy [195].

Evidence to support treatment recommendations.

Acrodermatitis chronica atrophicans does not appear to resolve

spontaneously. There are no prospective, randomized studies

on treatment. Oral or parenteral antimicrobial therapy (table

2) given for 3 weeks (range, 2–4 weeks) has resulted in im-

provement in pain and swelling, diminution in fibrous nodules,

and gradual fading of the lesion within 2–6 months [250–252].

Atrophic areas often persist, and little objective improvement

can be demonstrated in the neuropathy in uncontrolled studies,

regardless of whether antibiotics are administered parenterally.

However, progression of neurologic involvement is halted, and

the neuropathic symptoms of pain and paresthesia are im-

proved [251, 252]. In the United States, treatment of Lyme

disease–associated peripheral neuropathy with intravenous cef-

triaxone usually results in improvement. The reasons for the

differences in the experience with this manifestation of the

disease in the United States and Europe are not clear.

Recommendations

1. Available data indicate that acrodermatitis chronica

atrophicans may be treated with a 21-day course of the same

antibiotics (doxycycline [B-II], amoxicillin [B-II], or cefurox-

ime axetil [B-III]) used to treat patients with erythema migrans

(tables 2 and 3). A controlled study is warranted to compare

oral with parenteral antibiotic therapy for the treatment of

acrodermatitis chronica atrophicans.

POST–LYME DISEASE SYNDROMES

Primary management options considered. The focus of this

section is on patients with unexplained chronic subjective

symptoms following treatment with recommended antibiotic

regimens for a previous objective manifestation of Lyme disease

(e.g., erythema migrans). The management options considered

included oral versus parenteral antimicrobial therapy (includ-

ing prolonged treatment), versus symptomatic therapy only.

Outcomes evaluated. The panel weighed the potential ben-

efits and risks associated with antimicrobial therapy, including

adverse effects of antimicrobial therapy [241, 253] and com-

plications associated with the use of intravenous catheters

[254]. Also considered were the inconvenience of prolonged

therapies, the potential impact of the indiscriminate use of

antibiotics on the development of antibiotic resistance in the

community, and the economic costs [255]. The desired out-

come is to eliminate or alleviate symptoms without causing

harm to the patient.

Background and diagnosis of patients with post–Lyme dis-

ease syndromes. Shortly after treatment with conventional

courses of antibiotics for Lyme disease (tables 2 and 3), a mi-

nority of patients continue to report symptoms or signs. On

the basis of numerous studies of patients with erythema mig-

rans, it can be expected that few—if any—patients who are

compliant with antibiotic therapy will have persistence or re-

currence of the skin lesion. A rare patient, however, will develop

an objective extracutaneous manifestation of Lyme disease, such

as a new seventh nerve palsy or meningitis [138, 142]. Seventh

nerve palsy typically occurs during the first week of therapy

and, in most cases, appears to be benign; in an otherwise stable

patient, this event does not mandate a change in treatment

[138]. In contrast, if Lyme meningitis develops during or


shortly after completion of a course of oral antimicrobial ther-

apy, the patient should be re-treated with ceftriaxone or a com-

parable parenteral antibiotic (table 2) [142, 256].

In some patients treated for objective extracutaneous man-

ifestations of Lyme disease, there will be slow or even incom-

plete resolution of that manifestation. This is well illustrated

by the treatment of patients with neuroborreliosis who have

seventh nerve palsy. A small proportion of such patients will

have mild residual weakness of facial muscles [155]. A similar

phenomenon can probably occur with any other site of neu-

rologic impairment, attributable not to persistent infection but

to residual, irreversible neurologic damage. In ∼10% of patients

with Lyme arthritis, joint swelling (usually of a single joint)

will persist after recommended antimicrobial treatment courses

(table 3) [153, 205]. Chronic joint swelling in these circum-

stances, if not treated with other approaches (such as synov-

ectomy) [235], will eventually disappear, but it has lasted for

up to 4–5 years in a few patients [236]. B. burgdorferi has not

been demonstrated to persist in such patients.

Objective clinical manifestations are uncommon after treat-

ment of patients with Lyme disease. A much more likely sce-

nario after treatment is the persistence or development of sub-

jective symptoms without any residual or new objective

manifestation. In patients treated for early or late Lyme disease,

the frequency of subjective symptoms is at least partially de-

pendent on when after treatment the patient is assessed [142,

227]. On the basis of an intention-to-treat analysis of 1 study

of patients treated for erythema migrans, subjective symptoms

were present in 35% of patients at day 20, in 24% at 3 months,

and in 17% at 12 months ( , for the comparison of theP ! .002

frequency of symptoms across the 3 time points) [142]. The

presence of such symptoms during the first several weeks to

months after treatment most often appears to be due to slow

resolution of an inflammatory process associated with a highly

symptomatic or disseminated B. burgdorferi infection [257].

Furthermore, evidence from 3 randomized trials [137, 142, 227]

and 1 retrospective study [144] of patients treated for either

early or late Lyme disease indicates that a more prolonged initial

treatment course of antibiotics does not improve the rate of

resolution of symptoms (see the sections on early and late Lyme

disease above for more details).

In some patients, symptoms may be due, at least in part, to

a tickborne coinfection. When compared with patients with

Lyme disease alone, patients coinfected with babesiosis were

more symptomatic at the time of diagnosis and were more

likely to remain ill during the first 1–3 months or longer into

convalescence [24, 26]. Coinfection, however, does not appear

to worsen long-term outcome [258]. Furthermore, Babesia

coinfection is unlikely to explain persistent symptoms for the

majority of patients with Lyme disease because of the limited

geographic distribution of this zoonosis. The impact of coin-

fection with HGA on posttreatment symptoms is less clear than

for babesiosis. One report suggested that coinfected patients

also had a more delayed convalescence, but the number of study

subjects was small [26]. A second small study found little dif-

ference in symptom frequency for coinfected patients, com-

pared with those with Lyme disease alone [27]. A third study

found that HGA, with or without concurrent Lyme disease,

was associated with more fatigue and certain other symptoms

1–3 years after the onset of illness, compared with an uninfected

control group, but HGA was not associated with functional

disability [259]. Because of the lack of persistence of antibodies

to A. phagocytophilum, the authors of that study regarded this

process as a postinfectious syndrome of unknown etiology

[259]. Bartonella DNA has been found in some Ixodes species,

but there is no convincing evidence that Bartonella infections

can be transmitted to humans by a tick bite [260].

In many patients, posttreatment symptoms appear to be

more related to the aches and pains of daily living rather than

to either Lyme disease or a tickborne coinfection. Put simply,

there is a relatively high frequency of the same kinds of symp-

toms in “healthy” people. For example, 20%–30% of adults

complain of chronic fatigue [261–263], and in the 2003 Na-

tional Health Interview Survey, the frequency of doctor-diag-

nosed arthritis cases among adults was 21.5% [264]. A study

in England found a point prevalence of 11.2% for the presence

of self-reported chronic widespread pain among adults that was

frequently associated with feelings of depression and anxiety,

fatigue, and somatic symptoms [265]. A recent study of the

general adult United States population estimated a point prev-

alence of self-reported serious pain (level 3) to be 3.75%–

12.10%, depending on the assessment tool used; for level 3

emotional or cognitive dysfunction, it was 2.17%–3.42% [266].

Population-based surveillance in the United States indicates a

mean of 6.1 self-reported unhealthy days during the preceding

month [267]. Thus, the presence of arthralgia, myalgia, fatigue,

and other subjective symptoms after treatment for Lyme disease

must be evaluated in the context of “background” complaints

in a significant proportion of individuals.

Some patients with post–Lyme disease symptoms are found

to have multiple tender points on physical examination, in

addition to their reported widespread pain, and fulfill clinical

criteria for a diagnosis of fibromyalgia [268, 269]. Whether

Lyme disease triggered the fibromyalgia or whether the 2 con-

ditions coincided as simply the result of chance, given the rel-

atively high prevalence of fibromyalgia (2%) in the general

population [270, 271], is unknown and deserves further study.

A recent meta-analysis attempted to determine whether the

frequency of post–Lyme disease symptoms exceeds that of sim-

ilar symptoms in control groups without Lyme disease [272].

Because none of the prospective studies of the outcome of Lyme

disease included control populations, the authors of the meta-


analysis instead chose to analyze certain early retrospective

studies of patients principally diagnosed during the 1980s [273–

277]. The meta-analysis found that the frequency of post–Lyme

disease symptoms exceeded that of the control populations by

�5% [272]. Unfortunately, the findings of this meta-analysis

cannot be considered reliable, because the majority of the stud-

ies that were analyzed included “Lyme disease” cases that were

poorly characterized or were diagnosed on the basis of less-

reliable serologic testing methods than are currently recom-

mended [278, 279]. In addition, patients were included in these

studies who were not treated with antibiotics at all, who were

treated after a prolonged delay of months to years, or who were

treated with antibiotic regimens that are not currently rec-

ommended. Recall bias was also a potential limitation of the

studies evaluated, given the possibility that a person with Lyme

disease would be more likely to recall and/or to report sub-

sequent symptoms, such as arthralgias, myalgias, or fatigue,

than would another person with the same symptoms who was

never diagnosed with Lyme disease [280]. More recent pro-

spective studies of patients with Lyme disease have revealed

that outcome is substantially better than reported in studies

considered in the meta-analysis [87, 110, 139, 140, 142, 257,

278, 279]. Subjects in the prospective studies were well char-

acterized. Most had localized or disseminated early Lyme dis-

ease associated with erythema migrans (the most common pre-

sentation of definite B. burgdorferi infection [23, 88, 89]) and

were promptly treated with appropriate antibiotic regimens.

Moreover, in some of the prospective studies, posttreatment

symptoms occurred in !5% of patients [87, 110, 278]. A con-

trolled, prospective study would be preferable to a meta-analysis

for determination of whether the frequency of symptoms after

treatment for Lyme disease exceeds that of similar symptoms

in persons without Lyme disease.

Previous studies of various infectious diseases have suggested

that delayed convalescence can be related to the emotional state

of the patient before onset of the illness [281, 282]. In those

studies, fatigue was often a persistent symptom [281, 282].

Consistent with these observations, one study of patients with

Lyme disease found that poor outcome was associated with

prior traumatic psychological events and/or past treatment with

psychotropic medications [283]. This is an important consid-

eration for future investigations.

To summarize, it can be expected that a minority of patients

with Lyme disease will be symptomatic following a recom-

mended course of antibiotic treatment as a result of the slow

resolution of symptoms over the course of weeks to months

or as a result of a variety of other factors, such as the high

frequency of identical complaints in the general population.

Post–Lyme disease syndrome, posttreatment chronic Lyme

disease, and chronic Lyme disease. Post–Lyme disease syn-

drome, posttreatment chronic Lyme disease, and chronic Lyme

disease are terms intended to describe patients who have had

well-documented Lyme disease and who remain symptomatic

for many months to years after completion of appropriate an-

tibiotic therapy. Considerable confusion and controversy exist

over the frequency and cause of this process and even over its

existence. This is because of a lack of a standardized case def-

inition or a biologic marker to identify patients [284–287].

Some have classified untreated and treated patients with ob-

jective evidence of late Lyme disease, such as arthritis or en-

cephalopathy, as having chronic Lyme disease, instead of using

the preferred terminology of late Lyme disease. More often,

patients categorized as having post–Lyme disease syndrome

have subjective symptoms alone, such as musculoskeletal pains,

cognitive complaints, and/or fatigue without objective abnor-

malities on physical examination. Thus, it is not surprising that

studies of patients with post–Lyme disease complaints have

used different case definitions and enrollment criteria. Thus,

the study populations have varied.

The largest of the controlled treatment trials of patients with

post–Lyme disease complaints (which included separate treat-

ment studies for seropositive and seronegative patients) defined

post–Lyme disease syndrome as the presence of any of the

following symptoms: widespread musculoskeletal pain, cogni-

tive complaints, radicular pain, paresthesias, or dysesthesias,

provided the symptoms interfered with the ability to function

[288]. The symptoms also had to begin within 6 months after

the initial diagnosis and treatment of B. burgdorferi infection

and had to persist for at least 6 months. Although not a formal

component of the definition, 90% of the patients in this par-

ticular trial also complained of fatigue [289]. All patients in

this trial reported some cognitive impairment at baseline, and

170% gave cognitive dysfunction as their primary symptom

[290]. However, the study population had normal baseline neu-

ropsychological test scores, including objective measures of at-

tention and memory [290]. Although objective evidence of

cognitive dysfunction has been reported in patients with post–

Lyme disease symptoms [291, 292], these findings come from

a few relatively small studies in which there may have been

some degree of referral bias and/or differences in the neurop-

sychologic testing criteria used to diagnose cognitive impair-

ment [290, 293]. Standardization of a case definition for the

syndrome will be needed to address more specifically what

constitutes cognitive dysfunction and whether patients with

objective evidence of cognitive impairment should preferably

be classified as having late neurologic Lyme disease. Self-re-

ported cognitive dysfunction is clearly not a reliable indicator

of objective evidence of impairment based on neuropsycho-

logical testing [290].

In another published, controlled treatment trial of patients

with post–Lyme disease complaints, the case definition required

the presence of severe fatigue (as defined by a specific 11-


question fatigue severity scale), in which the onset coincided

with the diagnosis of Lyme disease and persisted for at least 6

months after the patients were originally treated with antibiotics

[294].

None of the published studies of patients with early or late

Lyme disease characterized partial responders using either of

the definitions above. Some of the prospective studies of the

treatment of early Lyme disease regarded patients as incomplete

responders if the patients had any unexplained subjective symp-

toms when they were assessed, regardless of symptom severity

or whether the symptoms necessarily originated within the first

6 months after initiation of antibiotic treatment [142, 257].

Unfortunately, it is apparent that the term “chronic Lyme

disease” is also being applied to patients with vague, undi-

agnosed complaints who have never had Lyme disease. When

adult and pediatric patients regarded as having chronic Lyme

disease have been carefully reevaluated at university-based med-

ical centers, consistently, the majority of patients have had no

convincing evidence of ever having had Lyme disease, on the basis

of the absence of objective clinical, microbiologic, or serologic evi-

dence of past or present B. burgdorferi infection [253, 268, 295–

298]. In one study, 150% of such patients actually had other

treatable disorders, such as depression, rheumatoid arthritis,

bursitis, and myasthenia gravis [253]. If serologic testing for

Lyme disease is done for chronically ill patients who only have

fatigue or musculoskeletal complaints without any objective

manifestation of Lyme disease, the test results have a poor

positive predictive value [98, 99, 101, 102, 104, 270]. Regardless

of the nature of the symptom(s), a low positive predictive value

can also be anticipated if serologic testing is done for patients

who do not reside in or travel to a geographic area where Lyme

disease is endemic. Under these circumstances, the majority of

patients with a positive test result will not have active B. burg-

dorferi infection and, accordingly, would be unlikely to obtain

a durable response from antibiotic treatment directed at this

infection. The fact that some antibiotic classes (e.g., tetracy-

clines and macrolides) have significant anti-inflammatory ef-

fects exclusive of their antimicrobial effects [299, 300] can ex-

plain, in part, why uninfected patients with inflammatory

conditions might also improve transiently while receiving these

drugs.

Do viable B. burgdorferi persist in tissues despite antibiotic

treatment? There is no convincing evidence in North Amer-

ica for the persistence of B. burgdorferi in the skin of humans

after treatment with antibiotic regimens known to be active

against B. burgdorferi in vitro. In the 2 US studies in which

this question has been investigated systematically, skin biopsy

samples from sites of a prior, resolved erythema migrans lesion

were cultured. In one study, none of 18 biopsy cultures for 13

patients with erythema migrans grew B. burgdorferi (5 patients

had negative skin biopsy culture results on 2 separate occasions

3–5 months apart), although all of these patients were culture

positive prior to treatment with an antibiotic [301]. In the

second study, 13 previously culture-positive patients were all

culture negative when an additional biopsy specimen from the

site of the resolved erythema migrans lesion was evaluated

[302].

In several other US studies, cultures were performed of var-

ious extracutaneous sites in patients with persistent symptoms

after antimicrobial therapy. One study reported the results of

blood cultures performed for 47 patients who had been exten-

sively treated with antimicrobials for symptoms of “chronic

Lyme disease” [303]. This study reported a 97% blood culture

positivity rate using a novel culture medium specifically re-

quiring Detroit tap water as a constituent. This publication did

not present the PCR data necessary to confirm that the visu-

alized spirochetal forms were actually B. burgdorferi. This was

an important omission, because the appearance of cellular de-

bris may be confused with spirochetes on microscopic exam-

ination of culture supernatants [304]. A subsequent study,

which evaluated 10 patients with post–Lyme disease symptoms

using the same novel culture method, in addition to standard

techniques for growing Lyme Borrelia, failed to grow B. burg-

dorferi from any blood culture [305]. In contrast to the con-

ventional medium used to grow Lyme Borrelia, the novel cul-

ture medium was also unable to support the growth of a

laboratory-adapted strain of B. burgdorferi for more than a few

days. Another study similarly was unsuccessful in recovering

B. burgdorferi from the blood of 12 patients with chronic post–

Lyme disease symptoms, using both conventional and hyper-

tonic media (M.S.K., unpublished data) [288]. The latter study

also cultured 128 CSF specimens for B. burgdorferi and eval-

uated blood specimens and CSF specimens by PCR. None of

the 843 specimens tested in total was either culture or PCR

positive [288, 289]. Therefore, the most plausible explanation

for the positive results using the novel blood culture method

reported by a single group of investigators [303] is that the

microscopic findings were not, in fact, due to B. burgdorferi.

In another study, B. burgdorferi DNA was detected by PCR

in urine samples of 74.2% of 97 United States patients who

were diagnosed as having “chronic Lyme disease” and who were

previously treated with antibiotics for extended periods of time

[306]. Few additional details were provided by the authors as

to the characteristics of the patient population. Because the

authors did not sequence the amplicons to confirm their iden-

tity, the results should be regarded as questionable in the ab-

sence of confirmation by other investigators. Nonspecific am-

plification in urine PCR using different targets has been

observed previously [103]. The results also appear to be in-

consistent with more recent assessments of the utility of PCR

for detection of B. burgdorferi DNA in urine samples, in which

the sensitivity of the assay was shown to be only 8% (1 of 12)


for untreated patients with objective evidence of Lyme disease

(erythema migrans) [307].

In one US study in which B. burgdorferi could be recovered

on culture after antibiotic treatment, the spirochete was cul-

tured from skin biopsy or blood samples from 5 (45%) of 11

patients with Lyme disease with persistent or recurrent ery-

thema migrans skin lesions, despite previous treatment with

cephalexin [133]. This result was not surprising, because ce-

phalexin, like other first-generation cephalosporins, is not ac-

tive in vitro against B. burgdorferi [125, 133]. The findings of

this study are also important, because they suggest that when

culture results are positive, there is likely to be concordance

with objective clinical failure.

Several studies in Europe have reported anecdotal instances

in which B. burgdorferi was recovered from specimens from

patients who had been treated with antimicrobials active against

this spirochete [308, 309]. In none of the studies, however,

could reinfection or laboratory contamination be excluded. In

a European study in which patient specimens were recultured

systematically to determine persistence of B. burgdorferi, the

spirochete was recovered from a skin biopsy sample of normal

appearing skin at the site of a resolved erythema migrans lesion

in 19 (1.7%) of 1148 patients; all of these patients also had a

positive culture result for a skin biopsy sample obtained prior

to antibiotic therapy [310]. Of the 5 cases in which isolates

from both the first and second biopsy samples were available

for analysis, plasmid and other typing methods suggested that

the isolates were not identical for at least 4 of the pairs [310].

In one case, the isolates were not even from the same species.

Strain differences might be interpreted as indicating reinfection

or possibly multiplicity of infecting borrelia in the original

infection [311, 312]. Unfortunately, the authors did not report

any data on the specificity of the culture technique. Without

this information or without confirmation of persistent infection

with an independent test method such as PCR, one cannot

exclude the possibility that a low frequency of culture contam-

ination had occurred. Culture contamination would be con-

sistent with the absence of clinical findings at the skin site, the

observation that the rate of positive culture results after re-

peated biopsy was similar regardless of which antibiotic class

the patient had received for treatment (F.S., unpublished data)

[313] and the lack of antibiotic resistance in the reisolated

borrelial strains [310, 313]. Culture contamination has occurred

before in laboratories growing B. burgdorferi (G.W., unpub-

lished data) and is a well-known phenomenon in laboratories

growing Mycobacterium tuberculosis [314].

The notion that symptomatic, chronic B. burgdorferi infec-

tion can exist despite recommended treatment courses of an-

tibiotics (tables 2 and 3) in the absence of objective clinical

signs of disease, is highly implausible as evidenced by (1) the

lack of antibiotic resistance in this genus [39, 40, 310], (2) the

lack of correlation of persistent symptoms with laboratory evi-

dence of inflammation or with the eventual development of

objective physical signs [223, 257, 288, 289], and (3) the lack

of precedent for such a phenomenon in other spirochetal in-

fections [315–317]. Additional compelling evidence against the

hypothesis that persistent symptoms are the result of persistent

infection is the fact that the concentrations of antibodies against

B. burgdorferi in many of these patients diminish to undetect-

able levels [257, 286, 288, 318]. The panel is unaware of any

chronic infection in which antibody titers diminish despite per-

sistence of the causative organism. In syphilis, patients who are

regarded as having treatment failure typically have persistent

or rising titers of antibodies [319]. Finally, Lyme disease lacks

characteristics of other infections that justify longer treatment

courses, such as infections in immunodeficient hosts, infections

in which a pathogen is inhibited but not killed by antimicrobial

therapy or in which available antimicrobials are minimally ac-

tive in vitro, infections caused by an intracellular pathogen,

infections involving a biofilm, infections on a heart valve, or

infections involving a clinical site in which there is ischemia,

a foreign body, a sequestrum, or frank pus [170]. The “cystic”

forms of B. burgdorferi that have been seen under certain

growth conditions in vitro have not been shown to have any

clinical significance [320].

Animal models may be useful to determine whether B. burg-

dorferi infection can persist despite antimicrobial treatment [36,

126, 321–327]. T1MIC appears to be the most relevant phar-

macodynamic parameter with regard to the killing action of b-

lactam antibiotics against B. burgdorferi and other spirochetes

[328, 329]. Consequently, the dose and pharmacokinetic pa-

rameters of the drug in animals would be expected to be in-

tegrally related to drug efficacy.

The importance of drug dosage on antibiotic efficacy is il-

lustrated by a study of gerbils in which 2 of 4 animals that

were treated with once-daily ceftriaxone at a dose of 50 mg/kg

remained culture positive, whereas B. burgdorferi could not be

recovered from any of the 8 animals that were treated with a

single daily dose of at least 200 mg/kg [126]. The importance

of pharmacokinetic parameters is illustrated by a study in which

2 different preparations of doxycycline were administered to

mice shortly after they had become infected with B. burgdorferi

by a tick bite. A single dose of doxycycline was 43% effective

in treating incubating B. burgdorferi infection when adminis-

tered orally to 13 mice, but it was 100% effective when ad-

ministered to 12 mice by a single subcutaneous injection of a

sustained release preparation of the drug [36]. Similar maxi-

mum plasma concentrations were achieved with either treat-

ment regimen, but by 48 h, doxycycline was absent from plasma

in orally treated animals, whereas low plasma concentrations

were maintained for 19 days in mice that were treated with the

sustained release preparation.


Studies indicate that antibiotics can cure B. burgdorferi in-

fection in infected animals [36, 126, 321–323]—even those that

are highly immunocompromised [321, 322]—but rare animals

may remain culture positive [324], and a substantial proportion

of animals will remain PCR positive in some [325–327], but

not all, studies [324]. The significance of continued PCR pos-

itivity needs to be better understood, but this phenomenon

should not necessarily be construed to indicate persistence of

viable B. burgdorferi. Unless proven otherwise, culture should

be regarded as the gold standard to address viability of B. burg-

dorferi [330, 331]. This is especially true for animal studies in

which access to tissues, both in amount and number of sites

examined, is not limiting. The studies also show no evidence

for recrudescence or persistence of clinical or histologic findings

of an active inflammatory process consistent with B. burgdorferi

infection when antibiotic-treated animals are immunosuppres-

sed [325, 327]. Therefore, even if a few residual B. burgdorferi

spirochetes or their DNA debris persist after antibiotic treat-

ment in animal systems, they no longer appear to be capable

of causing disease.

Possible failure to recapitulate the T1MIC found in humans

receiving antibiotic treatment is a potentially serious limitation

of almost all of the reported treatment studies of animals. In

patients receiving recommended courses of treatment, antibi-

otic levels would be expected to be sustained above the MIC

of B. burgdorferi for most of each 24-h period. For future studies

of animals to provide information more directly applicable to

the treatment of humans, dosing schedules will need to be

designed to address the often marked disparities in drug dis-

position between animals and humans.

Evidence to support treatment recommendations. Several

controlled treatment trials of patients with post–Lyme disease

symptoms have been published. The largest study consisted of

2 separate multicenter trials conducted between 1997 and 2000;

one trial included only patients who at the time of enrollment

were seropositive by IgG immunoblot, and the other included

only those who were seronegative [288]. The definition of post–

Lyme disease symptoms used by these investigators is men-

tioned above. In these double-blind studies, patients were ran-

domized to receive either intravenous ceftriaxone (2 g per day

for 30 days) followed by oral doxycycline (200 mg per day for

60 days) or matching intravenous and oral placebos. Both trials

combined had a target enrollment of 260 patients, but the data

and safety monitoring board recommended that the studies be

discontinued after a planned interim analysis. Statistical analysis

at that time indicated that a significant difference in treatment

efficacy favoring antimicrobial therapy would be unlikely if

additional patients were entered.

The primary outcome measure in these studies was im-

provement in the patients’ health-related quality of life, which

was measured by means of the medical outcome study 36-item

short-form General Health Survey (SF-36) [288]. Specimens of

CSF obtained at baseline and plasma specimens obtained at

baseline and at days 3, 5, 21, and 45 were tested by PCR for

the presence of B. burgdorferi DNA. CSF samples were cultured

for B. burgdorferi. Some blood samples were cultured for B.

burgdorferi in hypertonic medium.

A total of 129 patients were enrolled in the trials (78 were

seropositive, and 51 were seronegative) [288]. The average du-

ration of symptoms exceeded 4 years. None of the patients was

PCR or culture positive for B. burgdorferi. Serologic testing did

not suggest that coinfection with either B. microti or A. phag-

ocytophilum contributed to the patients’ symptoms [289].

Patients were assessed 6 months after study entry (3 months

after completion of the antibiotic regimens) [288]. There were

no significant differences in the primary outcome measure of

the health-related quality of life between the patients in the

antibiotic groups and those in the placebo groups in the se-

ropositive study, the seronegative study, or both studies com-

bined. Of note, 36% of patients in the combined placebo groups

had significant improvement in their SF-36 score, suggesting a

substantial placebo effect in this patient population. Although

deficits in physical health status (as measured by the SF-36)

for the patients enrolled were equivalent to those previously

found in patients with congestive heart failure or osteoarthritis,

it is important to point out that the entry criteria for the study

stipulated that the patients had to have symptoms that inter-

fered with normal functioning.

Although the patients in these trials uniformly reported cog-

nitive difficulties, the study population had normal baseline

neuropsychological test scores [290]. There was no significant

difference in degree of change in these scores between baseline

and later assessments at 90 and 180 days after study entry for

antibiotic- versus placebo-treated patients [290].

A smaller, single-center controlled treatment trial conducted

between 1997 and 1999 compared 28 days of intravenous cef-

triaxone with an identical-appearing placebo [294]. Entry cri-

teria required the presence of severe fatigue for �6 months, as

discussed above. On the basis of the hypothesis that the etiology

for this syndrome was inadequately treated neuroborreliosis,

there were 3 coprimary outcome measures: improvement in

the score on an 11-item fatigue questionnaire, improvement in

cognitive function, and clearance of OspA from CSF, an ex-

perimental measure of CSF infection. Fifty-five patients were

enrolled into the trial (28 in the ceftriaxone group and 27 in

the placebo group). Of the 512 patients screened by telephone,

most were excluded because of the absence of a documented

history of Lyme disease.

Fatigue improved in both groups at the 1-month assessment,

but improvement was sustained at 6 months only in the cef-

triaxone group [294]. There was no treatment effect in cognitive

function or in clearance of OspA from CSF. OspA was detected


in the CSF in only 16% of the patients in this study, a finding

contrary to the original study hypothesis that the patients had

active neuroborreliosis. The report is unclear as to whether the

patients had objective evidence of significant cognitive im-

pairment. The authors stated that the patients showed cognitive

slowing, compared with historical healthy control subjects, but

that the deficits were relatively mild. There was no significant

difference between groups in the degree of improvement in

fatigue or pain, as assessed by visual analogue scales in which

the patients were asked to record the intensity of these symp-

toms for the prior 2 weeks, or in perceived health changes using

the SF-36 health survey. Four (7%) of the patients experienced

a serious adverse event requiring hospitalization, including in-

travenous catheter sepsis in 3 patients and anaphylaxis in 1.

Several methodologic issues may have had a negative im-

pact on the validity of the findings in this study [294]. One

of these was the potential unmasking of patients noted by the

investigators, because patients receiving ceftriaxone were

more likely to guess their treatment group correctly. A second

concern was the loss of up to one-third of the on-study pa-

tients in the placebo group. Of the 27 patients randomized

to receive placebo, 3 withdrew prior to receipt of any treat-

ment, 3 (in retrospect) did not meet entry criteria for the

study, and 3 developed intravenous catheter sepsis and treat-

ment was prematurely discontinued.

The authors of this study concluded that repeated courses

of antibiotic treatment are not indicated for persistent symp-

toms following Lyme disease, including symptoms related to

fatigue and cognitive dysfunction, particularly in light of the

frequency of serious adverse events [294].

Another controlled treatment trial enrolled patients with per-

sistent cognitive symptoms, despite having been previously

treated for Lyme disease with at least 3 weeks of intravenous

antibiotics [332]. This study has been completed, but the results

have not been published. In this small trial, 37 patients were

randomized to receive 10 weeks of intravenous ceftriaxone (2

g per day) versus an intravenous placebo. Entry criteria differed

from previous studies [288, 294] because of the requirement

for the patients to have objective cognitive abnormalities, blur-

ring the distinction between Lyme encephalopathy and post–

Lyme disease syndrome, as discussed above. Preliminary find-

ings indicate the absence of sustained improvement in cognitive

function in the antibiotic-treated group at 14 weeks after ther-

apy, although some patients reported continued improvement

in physical functioning [332]. Of concern, 7 (18.9%) of the

study subjects experienced serious adverse events, the majority

of which were related to the intravenous catheter [332].

Several open-label studies have reported individual practi-

tioner’s experiences in treating chronic Lyme disease [318, 333,

334]. Open-label studies for an illness that has no objective

findings need to be viewed with a high degree of skepticism.

Moreover, many of these studies did not follow currently rec-

ommended standards for serologic testing for Lyme disease

[117] and were likely to have included patients who had never

been infected with B. burgdorferi. One report that might be

regarded as representative described 235 patients who were ill

for at least 3 months with any 2 of the following symptoms:

unexplained fatigue, neurological symptoms, or musculoskel-

etal symptoms [333]. Patients were treated with a macrolide

plus hydroxychloroquine for an indefinite period until the pa-

tient’s symptoms resolved or improved; a minimum course of

therapy was 3 months. Apparently, the rationale for this com-

bined regimen was the speculation that the reason chronic Lyme

disease is refractory to antibiotic therapy is that B. burgdorferi

is localized to an acidic endosome within some cell population.

The activity of the macrolide would be enhanced by alkalini-

zation of this endosomal compartment, which, in turn, would

be accomplished through the action of hydroxychloroquine. In

this study, ∼10% of patients were regarded as cured and slightly

more than 75% were regarded as improved after a median

duration of treatment of 6 months (range, 1–18 months). A

fundamental limitation of this study was that the data presented

did not convincingly demonstrate that the patients ever had

Lyme disease. Neither detection of borrelial antibody by 2-tier

serologic testing nor recommended interpretive criteria for im-

munoblots was used [117]. If patients without Lyme disease

were enrolled, which is likely, clinical improvement might have

been due in part to the anti-inflammatory properties of both

the macrolide [300] and hydroxychloroquine, rather than by

an antimicrobial effect. In addition, contrary to the study prem-

ise, most biologic data indicate that B. burgdorferi, like other

spirochetes, is principally an extracellular pathogen [335, 336].

Recommendations

1. There is no well-accepted definition of post–Lyme dis-

ease syndrome. This has contributed to confusion and contro-

versy and to a lack of firm data on its incidence, prevalence,

and pathogenesis. In an attempt to provide a framework for

future research on this subject and to reduce diagnostic am-

biguity in study populations, a definition for post–Lyme disease

syndrome is proposed in table 5. Whatever definition is even-

tually adopted, having once had objective evidence of B. burg-

dorferi infection must be a condition sine qua non. Further-

more, when laboratory testing is done to support the original

diagnosis of Lyme disease, it is essential that it be performed

by well-qualified and reputable laboratories that use recom-

mended and appropriately validated testing methods and in-

terpretive criteria [117, 118]. Unvalidated test methods (such

as urine antigen tests or blood microscopy for detection of

Borrelia species) should not be used [337].

2. To date, there is no convincing biologic evidence for

the existence of symptomatic chronic B. burgdorferi infection


Table 5. Proposed definition of post–Lyme disease syndrome.

Inclusion criteriaAn adult or child with a documented episode of early or late Lyme disease fulfilling the case definition of the Centers for Disease

Control and Prevention [112]. If based on erythema migrans, the diagnosis must be made and documented by an experienced healthcare practitioner.

After treatment of the episode of Lyme disease with a generally accepted treatment regimen [146] (tables 2 and 3), there is resolutionor stabilization of the objective manifestation(s) of Lyme disease.

Onset of any of the following subjective symptoms within 6 months of the diagnosis of Lyme disease and persistence of continuous orrelapsing symptoms for at least a 6 month period after completion of antibiotic therapy:FatigueWidespread musculoskeletal painComplaints of cognitive difficulties

Subjective symptoms are of such severity that, when present, they result in substantial reduction in previous levels of occupational,educational, social, or personal activities.

Exclusion criteriaAn active, untreated, well-documented coinfection, such as babesiosis.The presence of objective abnormalities on physical examination or on neuropsychologic testing that may explain the patient’s com-

plaints. For example, a patient with antibiotic refractory Lyme arthritis would be excluded. A patient with late neuroborreliosis associ-ated with encephalopathy, who has recurrent or refractory objective cognitive dysfunction, would be excluded.

A diagnosis of fibromyalgia or chronic fatigue syndrome before the onset of Lyme disease.A prolonged history of undiagnosed or unexplained somatic complaints, such as musculoskeletal pains or fatigue, before the onset of

Lyme disease.A diagnosis of an underlying disease or condition that might explain the patient’s symptoms (e.g., morbid obesity, with a body mass

index [calculated as weight in kilograms divided by the square of height in meters] �45; sleep apnea and narcolepsy; side effects ofmedications; autoimmune diseases; uncontrolled cardiopulmonary or endocrine disorders; malignant conditions within 2 years, exceptfor uncomplicated skin cancer; known current liver disease; any past or current diagnosis of a major depressive disorder with psy-chotic or melancholic features; bipolar affective disorders; schizophrenia of any subtype; delusional disorders of any subtype; demen-tias of any subtype; anorexia nervosa or bulimia nervosa; and active drug abuse or alcoholism at present or within 2 years).

Laboratory or imaging abnormalities that might suggest an undiagnosed process distinct from post–Lyme disease syndrome, such as ahighly elevated erythrocyte sedimentation rate (150 mm/h); abnormal thyroid function; a hematologic abnormality; abnormal levels ofserum albumin, total protein, globulin, calcium, phosphorus, glucose, urea nitrogen, electrolytes, or creatinine; significant abnormali-ties on urine analysis; elevated liver enzyme levels; or a test result suggestive of the presence of a collagen vascular disease.

Although testing by either culture or PCR for evidence of Borrelia burgdorferi infection is not required, should such testing be done byreliable methods, a positive result would be an exclusion.

among patients after receipt of recommended treatment regi-

mens for Lyme disease. Antibiotic therapy has not proven to

be useful and is not recommended for patients with chronic

(�6 months) subjective symptoms after administration of rec-

ommended treatment regimens for Lyme disease (E-I).

HGA

Primary management options considered. The management

options that were considered included oral or parenteral an-

timicrobial therapy for patients diagnosed with symptomatic

HGA.

Outcomes evaluated. The panel weighed both the risks and

consequences of developing acute and late complications of

HGA and the economic costs and possible adverse effects of

antimicrobial therapy. The desired outcome is to resolve the

symptoms and signs of HGA while minimizing the adverse

effects of antimicrobial therapy.

Background and diagnosis of HGA. HGA is a rickettsial

infection of neutrophils [338, 339]. The infectious agent, A.

phagocytophilum, is transmitted by the bite of infected Ixodes

ticks, and human infection occurs in areas in the United States

and Europe where Lyme disease is endemic [340–343]. In con-

trast to Lyme disease, however, HGA is infrequently diagnosed

in children.

Clinical manifestations are nonspecific and may include fe-

ver, chills, headache, and myalgias [94, 95, 341–344]. The in-

cubation period is 5–21 days [344]. Laboratory features may

include leukopenia, lymphopenia, thrombocytopenia, and mild

elevation of liver enzyme levels. In most cases, HGA is a mild,

self-limited illness, and all clinical signs and symptoms resolve

in most patients within 30 days, even without antibiotic therapy

[340]. However, serious manifestations of infection, including

a fatal outcome, have been reported in patients with factors

known to suppress the immunologic response to infection, such

as advanced age, immunosuppressive therapy, chronic inflam-

matory illnesses, or underlying malignant diseases [340, 345,

346]. Chronic infection due to A. phagocytophilum has not been

described in humans.

Prior to initiation of antibiotic therapy, A. phagocytophilum


can be detected in blood samples by smear examination, PCR,

or culture using HL60 cells [94, 345, 347–349]. Identification

of the characteristic intragranulocytic inclusions on blood

smear is the most rapid diagnostic method, but such inclusions

are often scant in number or sometimes absent; in addition,

other types of inclusions unrelated to HGA, or overlying plate-

lets, can be misinterpreted by inexperienced observers [349].

The most sensitive diagnostic method is acute-phase and con-

valescent-phase serologic testing using an indirect fluorescent

antibody assay (acute-phase testing alone is not sufficiently

sensitive) [348–350]. Serologic testing is often the only way to

diagnose a patient who has already begun to receive antibiotic

treatment. Immunostaining of A. phagocytophilum antigen in

a tissue sample is an uncommonly used diagnostic modality

[344]. Doxycycline therapy leads to clinical improvement in

24–48 h [340, 345, 346, 351]. Thus, patients who do not re-

spond to treatment within this time frame should be reeval-

uated for alternative diagnoses and treatment, including coin-

fection with B. microti in certain geographic areas (see

Babesiosis below).

Evidence to support treatment recommendations. There

are no controlled clinical trials on the use of antibiotics for

treatment of HGA. Doxycycline and rifampin are both highly

active against A. phagocytophilum in vitro [352–354], and rec-

ommendations for therapy have been based on published re-

ports of the clinical response to these drugs. It is generally

accepted that all symptomatic patients should be treated with

an appropriate antimicrobial agent, because it may be very

difficult to distinguish patients who will have a self-limited

illness from those who will develop a complicated or fatal

course of HGA [351].

Most of the clinical experience in treatment of adults has

been with doxycycline at a dosage of 100 mg twice per day

given orally [340, 345, 351]. There is only limited experience

in the use of doxycycline for treatment of HGA in children

[355–360] or pregnant women [357]. Doxycycline was used

successfully to treat a pregnant woman who developed symp-

tomatic HGA during parturition [357]. Her newborn child was

subsequently diagnosed with HGA and was also treated suc-

cessfully with doxycycline. In addition, a 5-year-old boy, who

had simultaneous HGA and Lyme disease, was treated suc-

cessfully with doxycycline [359]. Recently a 38-year-old woman

was diagnosed with HGA 10 days after she had delivered a

healthy baby [355]. She was treated with doxycycline for 2

weeks while breast-feeding, and both mother and baby were

well at a later follow-up examination. Although the American

Academy of Pediatrics has recommended doxycycline as the

preferred antibiotic for treatment of children diagnosed with

clinically apparent HGA [361], a small number of pediatric-

age patients and pregnant women have also been treated suc-

cessfully with rifampin [358, 362, 363].

The optimal duration of antimicrobial therapy for HGA has

not been established. At first, patients were treated empirically

with doxycycline for 10–14 days, and the recommendations for

duration of treatment followed the guidelines for treatment of

Lyme disease. Clinical experience, however, has shown that

adult patients who have been treated for 7–10 days experienced

complete resolution of their infections, and relapse or chronic

infection has not been demonstrated [27, 94, 95, 341, 343]. A

shorter course of doxycycline (4–7 days) has been advocated

for patients !8 years of age because of the potential risk for

adverse effects from this drug (dental staining) in young chil-

dren [340, 351, 364, 365].

There is no published clinical experience on the use of clar-

ithromycin or azithromycin for treatment of HGA. Certain

fluoroquinolones, such as levofloxacin, are active against A.

phagocytophilum in vitro [352–354], but a single case report

and a small study of immunodeficient mice (severe combined

immune deficient [SCID]) have suggested that this class of

drugs may not be curative of infection [366]. Chloramphenicol

is inactive against A. phagocytophilum in vitro [352–354] and

has been ineffective for treatment of horses infected with A.

phagocytophilum [367].

Recommendations

1. All symptomatic patients suspected to have HGA

should be treated with antimicrobial therapy because of the

risk of complications (A-III). Suspicion for HGA is based on

the acute onset of unexplained fever, chills, and headache, often

in association with thrombocytopenia, leukopenia, and/or in-

creased liver enzyme levels in patients with exposure to I. sca-

pularis or I. pacificus ticks within the prior 3 weeks. Confir-

mation of the diagnosis is based on laboratory testing (see

above), but antibiotic therapy should not be delayed in a patient

with a suggestive clinical presentation pending the results.

2. Doxycycline is recommended as the treatment of choice

for patients who are suspected to have symptomatic HGA (A-

II). The dosage regimen for adults is 100 mg given twice per

day by mouth (or intravenously for those patients unable to

take an oral medication) for 10 days. This treatment regimen

should be adequate therapy for patients with HGA alone and

for patients who are coinfected with B. burgdorferi.

Although a 10-day treatment course of doxycycline may be

offered to all children as well (C-III), the panel preferred a

modified approach in which severity of illness, age of the child,

and the presence or absence of coinfection with B. burgdorferi

were each considered to minimize an already low risk of drug

toxicity [365]. The suggested dosage of doxycycline for children

with HGA is 4 mg/kg per day in 2 divided doses (maximum,

100 mg per dose) given orally (or intravenously for children

unable to take an oral medication). Children at least 8 years

of age may be treated with a 10-day course of doxycycline. For


severely ill children !8 years of age without concomitant Lyme

disease, the panel recommended an abbreviated treatment

course of 4–5 days (i.e., for ∼3 days after resolution of fever)

(B-III). Children treated with an abbreviated course of therapy

should be closely observed to ensure resolution of clinical and

laboratory abnormalities. If the child has concomitant Lyme

disease, then amoxicillin (50 mg/kg per day in 3 divided doses;

maximum, 500 mg per dose) or cefuroxime axetil (30 mg/kg

per day in 2 divided doses; maximum, 500 mg per dose) should

be initiated at the conclusion of the course of doxycycline to

complete a 14-day total course of antibiotic therapy (B-III).

Recommended management of less-severely ill children with

HGA is discussed below.

3. Patients with mild illness due to HGA who are not

optimally suited for doxycycline treatment due to a history of

drug allergy, pregnancy, or age !8 years, may be treated with

rifampin for 7–10 days using a dosage regimen of 300 mg twice

per day by mouth for adults and 10 mg/kg twice per day for

children (maximum, 300 mg per dose) (B-III). Rifampin-

treated patients should be closely observed to ensure resolution

of clinical and laboratory abnormalities. Because rifampin is

not effective therapy for Lyme disease, coinfected patients

should also be treated with amoxicillin or cefuroxime axetil as

used for the treatment of erythema migrans (see tables 2 and

3) (A-I). No other antimicrobial can be recommended for the

treatment of HGA (E-III).

4. Persistence of fever for 148 h after initiation of dox-

ycycline suggests that the diagnosis of HGA is incorrect or,

more remotely, that the patient is coinfected with B. microti.

5. Treatment is not recommended for asymptomatic in-

dividuals who are seropositive for antibodies to A. phagocyto-

philum (E-III).

BABESIOSIS

Primary management options considered. The management

options considered included oral or parenteral antimicrobial

therapy and exchange transfusion for patients diagnosed with

symptomatic babesiosis.

Outcomes evaluated. The panel weighed both the risks and

consequences of developing acute and late complications of

babesiosis and the economic costs and possible adverse effects

of antimicrobial therapy and exchange transfusion. The desired

outcome is to resolve the symptoms and signs of babesiosis

and prevent relapse while minimizing the adverse effects of

both antimicrobial therapy and exchange transfusion.

Background and diagnosis of babesiosis. Babesiosis is

caused by intraerythrocytic protozoa. Although several different

species of Babesia have been found to infect humans, B. microti

is the most common cause of infection in the United States.

B. microti is transmitted by I. scapularis ticks, which may also

transmit B. burgdorferi and A. phagocytophilum [368–370]. In-

fection due to B. microti occurs in parts of New England, New

York State, New Jersey, Minnesota, and Wisconsin [368–371].

Infection has been recognized, however, in a only limited por-

tion of the geographic areas where Lyme disease is endemic,

and the number of reported cases of babesiosis is less than that

of Lyme disease in these areas [372]. High-incidence areas in-

clude coastal southern New England and the chain of islands

off the coast that include Martha’s Vineyard and Nantucket

Island, MA; Block Island, RI; and eastern Long Island and

Shelter Island, NY.

Other species of Babesia have been found to cause disease

in California and Washington State (WA-1) and Missouri (MO-

1) [373, 374]. Sporadic cases of babesiosis have also been re-

ported in Europe (Babesia divergens and B. microti), Africa,

Asia, and South America [375–379].

The clinical features of babesiosis are similar to those of

malaria and range in severity from asymptomatic to rapidly

fatal. Most patients experience a viral infection–like illness with

fever, chills, sweats, myalgia, arthralgia, anorexia, nausea, vom-

iting, or fatigue [24, 96, 371–375, 380–384]. On physical ex-

amination, fever, splenomegaly, hepatomegaly, or jaundice may

be observed [371, 380, 381, 384]. Laboratory findings may

include hemolytic anemia with an elevated reticulocyte count,

thrombocytopenia, proteinuria, and elevated levels of liver en-

zymes, blood urea nitrogen, and creatinine [96, 380, 381]. Com-

plications of babesiosis include acute respiratory failure, dis-

seminated intravascular coagulation, congestive heart failure,

coma, and renal failure [96, 381]. Immunocompromised pa-

tients, such as those who lack a spleen, have a malignancy or

HIV infection, or who exceed 50 years of age, are at increased

risk of severe babesiosis [381–383]. Approximately one-quarter

of infected adults and one-half of children experience asymp-

tomatic infection or such mild viral–like illness that the infec-

tion is only incidentally diagnosed by laboratory testing [372,

384–386]. In both untreated and treated patients, parasitemia

may occasionally persist, resulting either in subsequent recru-

descence weeks or months later (primarily in immunocom-

promised hosts) or, rarely, in transmission of the pathogen to

others through blood transfusion [387, 388].

The diagnosis of babesiosis is based on epidemiologic, clin-

ical, and laboratory information. Babesiosis only occurs in pa-

tients who live in or travel to areas of endemicity or who have

received a blood transfusion containing the parasite within the

previous 9 weeks [388]. Because the clinical findings are non-

specific, laboratory studies are necessary to confirm the diag-

nosis. Specific diagnosis of babesiosis is made by microscopic

identification of the organism on Giemsa stains of thin blood

smears [389]. On thick blood smears, the organisms appear as

simple chromatin dots that might be mistaken for stain pre-

cipitate or iron inclusion bodies. Consequently, this method


should only be performed by someone with extensive experi-

ence in interpreting thick smears. Multiple blood smears should

be examined, because only a few erythrocytes may be infected

in the early stage of the illness when most people seek medical

attention. Because Babesia species may be confused with ma-

larial parasites on blood smear, confirmation of the diagnosis

and identification of the specific babesial pathogen may require

additional laboratory testing. Also, it is important to have other

supportive laboratory results if only a few ring-like structures

are observed by microscopy. Both IgG and IgM antibodies to

Babesia can be detected by indirect fluorescent antibody assay

[390, 391]. Virtually all infected patients will have detectable

antibodies in an acute-phase serum sample or a convalescent-

phase sample obtained 4–6 weeks later. PCR detection of Ba-

besia DNA in blood has been shown to be slightly more sensitive

than microscopic detection of parasites on blood smear [392,

393].

In summary, the diagnosis of babesiosis is most reliably made

in patients who have lived in or traveled to an area where

babesiosis is endemic, experience viral infection–like symp-

toms, and have identifiable parasites on blood smear and anti-

babesial antibody in serum. The diagnosis of active babesial

infection based on seropositivity alone is suspect. PCR is a

useful laboratory adjunct, but as with smear and antibody test-

ing, it should only be performed in laboratories that are ex-

perienced in such testing and meet the highest laboratory per-

formance standards.

Evidence to support treatment recommendations. The

combination of clindamycin and quinine was initially used in

1982 to treat a newborn infant with transfusion-transmitted

babesiosis and subsequently became the first widely used an-

timicrobial therapy for human babesiosis [394, 395]. This com-

bination, however, is frequently associated with untoward re-

actions, such as tinnitus, vertigo, and gastrointestinal upset

[382, 387, 396]. These adverse effects were substantive enough

to prompt earlier recommendations that treatment of babesiosis

be reserved for seriously ill patients and that less ill patients

should be observed without therapy [395]. Treatment failures

have been reported in patients who have had splenectomy, HIV

infection, or concurrent corticosteroid therapy [373, 382, 397].

The successful use of atovaquone and azithromycin for treat-

ing malaria in humans and babesiosis in a hamster infection

model suggested that this drug combination might also be use-

ful for treatment of human babesiosis [398, 399]. Atovaquone

and azithromycin were compared with clindamycin and qui-

nine in a prospective, nonblinded, randomized therapeutic trial

of 58 adult patients with non–life-threatening babesiosis [396].

Atovaquone (750 mg every 12 h) plus azithromycin (500 mg

on day 1, then 250 mg per day thereafter) was found to be as

effective in clearing parasitemia and resolving symptoms as the

combination of clindamycin (600 mg every 8 h) and quinine

(650 mg every 8 h). Both drug combinations were given orally

for 7 days. After 3 months, there was no evidence of parasites

on blood smear or amplifiable B. microti DNA in either group.

Significantly fewer adverse effects were associated with the ato-

vaquone and azithromycin combination. Three-fourths of pa-

tients receiving clindamycin and quinine experienced adverse

drug reactions, and one-third had to decrease the dose or dis-

continue the medication. In contrast, only 15% of patients in

the azithromycin and atovaquone group were noted to have

adverse effects from the drugs, and only 1 patient required a

decrease in dosage or discontinuation of medication. It was

concluded that the atovaquone and azithromycin drug com-

bination was preferable to the combination of clindamycin and

quinine because of improved tolerability [396]. For immuno-

compromised patients with babesiosis, successful outcome has

been reported using atovaquone combined with higher doses

of azithromycin (600–1000 mg per day) [400].

Other antimicrobials have been used to treat babesiosis. The

combination of pentamidine and trimethoprim-sulfamethox-

azole was found to be moderately effective in clearing parasi-

temia and symptoms due to B. divergens [401]. Potential ad-

verse reactions of pentamidine, however, limit the use of this

combination. Azithromycin, in combination with quinine, was

used successfully in 2 patients who had not improved after

clindamycin and quinine therapy [402, 403]. A severely im-

munosuppressed HIV-infected patient with chronic babesiosis

who did not respond to clindamycin and quinine was suc-

cessfully treated with clindamycin, doxycycline, and azithro-

mycin [382].

Partial or complete RBC exchange transfusion is a potentially

life-saving adjunct to antimicrobial therapy and is indicated for

patients with high-grade parasitemia (�10%), significant he-

molysis, or renal, hepatic, or pulmonary compromise [381, 404,

405]. There are, however, no published trials systematically

comparing antimicrobial therapy alone with the combination

of antimicrobial therapy and exchange transfusion.

Recommendations

1. All patients with active babesiosis should be treated

with antimicrobial therapy because of the risk of complications

(A-III). Diagnostic criteria for active babesial infection should

include the presence of viral infection–like symptoms and iden-

tification of babesial parasites in blood by smear evaluation or

by PCR amplification of babesial DNA. Symptomatic patients

whose serum contains antibody to Babesia but whose blood

lacks identifiable babesial parasites on smear or babesial DNA

by PCR should not receive treatment (E-III). Treatment is also

not recommended for asymptomatic individuals regardless of

the results of serologic tests, blood smears, or PCR (E-III).

Asymptomatic patients with positive babesial smear and/or

PCR results should have these studies repeated, and a course


of treatment should be considered if parasitemia persists for

13 months (B-III).

2. The combination of either atovaquone plus azithro-

mycin or clindamycin plus quinine for 7–10 days is the initial

therapy that should be considered for patients with babesiosis

(A-I). Clindamycin and quinine should be given to those with

severe babesiosis (A-III). In such patients, clindamycin should

be administered intravenously rather than orally, and exchange

transfusion should be considered (see below). Longer duration

of antimicrobial therapy may be necessary in highly and per-

sistently symptomatic patients until parasitemia is cleared, but

no controlled studies exist that define the risk-benefit ratio of

more prolonged therapy.

The dosage regimen of atovaquone plus azithromycin for

adults is atovaquone, 750 mg orally every 12 h, and azithro-

mycin, 500–1000 mg on day 1 and 250 mg once per day there-

after by the oral route. For immunocompromised patients with

babesiosis, higher doses of azithromycin (600–1000 mg per day)

may be used. The doses for children are atovaquone, 20 mg/

kg every 12 h (up to a maximum of 750 mg per dose), and

azithromycin, 10 mg/kg per day once per day on day 1 (up to

a maximum of 500 mg per dose) and 5 mg/kg once per day

(up to a maximum of 250 mg per dose) thereafter orally.

The dosage regimen of clindamycin plus quinine for adults

is clindamycin, 300–600 mg every 6 h intravenously or 600 mg

every 8 h orally, and quinine, 650 mg every 6–8 h orally. Doses

for children are clindamycin, 7–10 mg/kg given every 6–8 h

(up to a maximum of 600 mg per dose) intravenously or orally,

and quinine, 8 mg/kg given every 8 h (up to a maximum of

650 mg per dose) orally.

3. Partial or complete RBC exchange transfusion is in-

dicated for those with severe babesiosis, as indicated by high-

grade parasitemia (�10%), significant hemolysis, or renal, he-

patic, or pulmonary compromise (A-III). No data are available

to determine whether partial exchange transfusion is preferable

to whole blood exchange; expert consultation with an infectious

diseases expert and a hematologist is recommended.

4. Patients with moderate-to-severe babesiosis should be

monitored closely during therapy to ensure clinical improve-

ment and improvement of parasitemia and other laboratory

abnormalities (A-III). In patients with mild-to-moderate ba-

besiosis, clinical improvement should occur within 48 h after

antiprotozoal therapy is begun, and symptoms should com-

pletely resolve within 3 months of initiation of therapy. In

severely ill patients, the hematocrit and percentage of parasit-

ized erythrocytes should be monitored daily or every other day

until the patient has improved and the level of parasitemia has

decreased to !5% of erythrocytes. Some patients may have

persistence of low-grade parasitemia for months after specific

antimicrobial therapy.

5. Physicians should consider the possibility of coinfec-

tion with B. burgdorferi or A. phagocytophilum or both in pa-

tients with especially severe or persistent symptoms, despite

appropriate antibabesial therapy (A-III). Patients found to have

coinfection should be treated with additional antimicrobial

therapy, as described in the sections above on early Lyme disease

or HGA. An underlying immunodeficiency (including asplenia

or prior splenectomy, malignancy, and HIV infection) also

should be considered in patients with severe or prolonged ep-

isodes of babesiosis.

6. Re-treatment of patients with antibabesial therapy, as

outlined above, should be considered if babesial parasites or

amplifiable babesial DNA is detected in blood �3 months after

initial therapy, regardless of symptom status (A-III). However,

such assays need not be done routinely for immunocompetent

patients who are asymptomatic.

Acknowledgments

We thank Lisa Giarratano and Richard Minott for assistance in thepreparation of this manuscript. The following individuals served as con-sultants to the Infectious Diseases Society of America panel in the devel-opment of these guidelines: Maria Aguero-Rosenfeld, Stephen W. Barthold,Susan O’Connell, Volker Fingerle, Jerry Green, Barbara J. Johnson, RichardKaplan, Jooyun Lee, Muhammad Morshed, Jose Munoz, Benjamin H. Na-telson, John Nowakowski, Mario Philipp, Joseph F. Piesman, Arthur Wein-stein, and Bettina Wilske. The Expert Panel also wishes to express itsgratitude to Paul G. Auwaerter, Michael A. Gerber, and Leonard H. Sigalfor their thoughtful review of an earlier draft of these guidelines.

Potential conflicts of interest. G.P.W. has received consulting fees fromBaxter and research support from Immunetics, and he is a founder ofDiaspex, a company that does not offer products or services. R.J.D. hasserved as a speaker for Pfizer and is part owner of Biopeptides, a biotechcompany that develops vaccines and laboratory diagnostics, including prod-ucts for Borrelia burgdorferi. J.J.H. has served as an expert witness on behalfof Lymerix (GlaxoSmithKline). A.C.S. has received consulting fees fromBaxter. P.J.K. has a patent pending with a university on a babesiosis di-agnostic procedure that is not yet on the market. All other authors: noconflicts.

References

1. Wormser GP, Fish D. Lyme disease. In: Baddour L, Gorbach SL, eds.Therapy of infectious diseases. Philadelphia: Saunders, 2003:697–719.

2. Panel on Clinical Practices for Treatment of HIV Infection. Guidelinesfor the use of antiretroviral agents in HIV-1 infected adults and ad-olescents: April 7, 2005. Available at: http://www.AIDSinfo.nih.gov/.Accessed 1 August 2005.

3. Gross PA, Barrett TL, Dellinger EP, et al. Purpose of quality standardsfor infectious diseases. Clin Infect Dis 1994; 18:421.

4. Centers for Disease Control and Prevention. Lyme disease–UnitedStates, 2001–2002. MMWR Morb Mortal Wkly Rep 2004; 53:365–9.

5. Centers for Disease Control and Prevention. Summary of notifiablediseases—United States, 2003. MMWR Morb Mortal Wkly Rep2005; 52(Suppl):1–85.

6. Hayes EB, Piesman J. How can we prevent Lyme disease? N Engl JMed 2003; 348:2424–30.

7. Needham GR. Evaluation of five popular methods for tick removal.Pediatrics 1985; 75:997–1002.

8. Stjernberg L, Berglund J. Detecting ticks on light versus dark clothing.Scand J Infect Dis 2005; 37:361–4.

9. Fishbein DB, Dennis DT. Tick-borne diseases—a growing risk. N EnglJ Med 1995; 333:452–3.


10. Fradin MS. Mosquitoes and mosquito repellents: a clinician’s guide.Ann Intern Med 1998; 128:931–40.

11. US Environmental Protection Agency, Office of Pesticide Programs.Using insect repellents safely (EPA-735/F-93-052R). Washington, DC:US Environmental Protection Agency, 1996.

12. Carroll JF, Klun JA, Debboun M. Repellency of DEET and SS220applied to skin involves olfactory sensing by two species of ticks. MedVet Entomol 2005; 19:101–6.

13. Centers for Disease Control. Seizures temporally associated with useof DEET insect repellent: New York and Connecticut. MMWR MorbMortal Wkly Rep 1989; 38:678–80.

14. Insect repellents. Med Lett Drug Ther 2003; 45:41–2.15. Koren G, Matsui D, Bailey B. DEET-based insect repellents: safety

implications for children and pregnant and lactating women. CMAJ2003; 169:209–12.

16. Taplin D, Meinking TL. Pyrethrins and pyrethroids in dermatology.Arch Dermatol 1990; 126:213–21.

17. Insect repellents. Med Lett Drug Ther 1989; 31:45–7.18. Picaridin—a new insect repellent. Med Lett Drug Ther 2005; 47:46–7.19. Vazquez M, Cartter MJ, Shapiro ED. Effectiveness of personal pro-

tective measures for Lyme disease [abstract 1866]. Pediatr Res 2003;53:327A.

20. Poland GA. Prevention of Lyme disease: a review of the literature.Mayo Clin Proc 2001; 76:713–24.

21. Wormser GP. Prevention of Lyme borreliosis. Wien Klin Wochenschr2005; 117:385–91.

22. Ley C, Olshen EM, Reingold AL. Case-control study of risk factorsfor incident Lyme disease in California. Am J Epidemiol 1995;142(Suppl 9):S39–47.

23. Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lymedisease with recombinant Borrelia burgdorferi outer-surface lipopro-tein A with adjuvant. N Engl J Med 1998; 339:209–15.

24. Krause PJ, Telford SR III, Spielman A, et al. Concurrent Lyme diseaseand babesiosis: evidence for increased severity and duration of illness.JAMA 1996; 275:1657–60.

25. Nadelman RB, Horowitz HW, Hsieh T-C, et al. Simultaneous humanehrlichiosis and Lyme borreliosis. N Engl J Med 1997; 337:27–30.

26. Krause PJ, McKay K, Thompson CA, et al. Disease-specific diagnosisof coinfecting tick-borne zoonoses: babesiosis, human granulocyticehrlichiosis, and Lyme disease. Clin Infect Dis 2002; 34:1184–91.

27. Belongia EA, Reed KD, Mitchell PD, et al. Clinical and epidemio-logical features of early Lyme disease and human granulocytic ehr-lichiosis in Wisconsin. Clin Infect Dis 1999; 29:1472–7.

28. Steere AC, McHugh G, Suarez C, Huitt J, Damle N, Sikand VK.Prospective study of coinfection in patients with erythema migrans.Clin Infect Dis 2003; 36:1078–81.

29. Campbell GL, Fritz CL, Fish D, Nowakowski J, Nadelman RB, Worm-ser GP. Estimation of the incidence of Lyme disease. Am J Epidemiol1998; 148:1018–26.

30. Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodesscapularis tick bite. N Engl J Med 2001; 345:79–84.

31. Costello CM, Steere AC, Pinkerton RE, Feder HM Jr. A prospectivestudy of tick bites in an endemic area for Lyme disease. J Infect Dis1989; 159:136–9.

32. Shapiro ED, Gerber MA, Holabird ND, et al. A controlled trial ofantimicrobial prophylaxis for Lyme disease after deer-tick bites. NEngl J Med 1992; 327:1769–73.

33. Agre F, Schwartz R. The value of early treatment of deer tick bite forthe prevention of Lyme disease. Am J Dis Child 1993; 147:945–7.

34. Warshafsky S, Nowakowski J, Nadelman RB, Kamer RS, Peterson SJ,Wormser GP. Efficacy of antibiotic prophylaxis for prevention of Lymedisease: a meta-analysis. J Gen Intern Med 1996; 11:329–33.

35. Takafuji ET, Kirkpatrick JW, Miller RN, et al. An efficacy trial ofdoxycycline chemoprophylaxis against leptospirosis. N Engl J Med1984; 310:497–500.

36. Zeidner NS, Brandt KS, Dadey E, Dolan MC, Happ C, Piesman J.Sustained-release formulation of doxycycline hyclate for prophylaxisof tick bite infection in a murine model of Lyme borreliosis. Anti-microb Agents Chemother 2004; 48:2697–9.

37. Lee J, Nowakowski J, Nadelman RB, Wormser GP. What amoxicillinregimen is predicted to be equivalent to a single 200 mg oral doseof doxycycline for prevention of Lyme borreliosis [abstract P208]? In:Program and abstracts of the 10th International Conference on LymeBorreliosis and Other Tick-borne Diseases (Vienna, Austria). AustrianSociety for Hygeine, Microbiology, and Preventive Medicine, 2005:122.

38. Magid D, Schwartz B, Craft J, Schwartz JS. Prevention of Lyme diseaseafter tick bites—a cost effectiveness analysis. N Engl J Med 1992; 327:534–41.

39. Nowakowski J, Wormser GP. Treatment of early Lyme disease: infec-tion associated with erythema migrans. In: Coyle PPK, ed. Lymedisease. St. Louis: Mosby-Year Book, 1993:149–62.

40. Hunfeld K-P, Kraiczy P, Kekoukh E, Schafer V, Brade V. Standardizedin vitro susceptibility testing of Borrelia burgdorferi against well-known and newly developed antimicrobial agents—possible impli-cations for new therapeutic approaches to Lyme disease. Int J MedMicrobiol 2002; 291(Suppl 33):125–37.

41. Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ. Amox-icillin plus probenecid versus doxycycline for treatment of erythemamigrans borreliosis. Lancet 1990; 336:1404–6.

42. Massarotti EM, Luger SW, Rahn DW, et al. Treatment of early Lymedisease. Am J Med 1992; 92:396–403.

43. Luft BJ, Dattwyler RJ, Johnson RC, et al. Azithromycin comparedwith amoxicillin in the treatment of erythema migrans: a double blind,randomized, controlled trial. Ann Intern Med 1996; 124:785–91.

44. Steere AC, Levin RE, Molloy PJ, et al. Treatment of Lyme arthritis.Arthritis Rheum 1994; 37:878–88.

45. Maraspin V, Lotric-Furlan S, Strle F. Development of erythema mig-rans in spite of treatment with antibiotics after a tick bite. Wien KlinWochenchr 2002; 114:616–9.

46. Schlesinger PA, Duray PH, Burke SA, Steere AC, Stillman MT. Ma-ternal-fetal transmission of the Lyme disease spirochete, Borrelia burg-dorferi. Ann Intern Med 1985; 103:67–8.

47. Maraspin V, Cimperman J, Lotric-Furlan S, Pleterski-Rigler D, StrleF. Treatment of erythema migrans in pregnancy. Clin Infect Dis1996; 22:788–93.

48. Williams CL, Strobino B, Weinstein A, Spierling P, Medici F. MaternalLyme disease and congenital malformation: a cord blood serosurveyin endemic and control areas. Paediatr Perinat Epidemiol 1995; 9:320–30.

49. Strobino BA, Williams CL, Abid S, Chalson R, Spierling P. Lymedisease and pregnancy outcome: a prospective study of two thousandprenatal patients. Am J Obstet Gynecol 1993; 169:367–74.

50. Shapiro ED, Gerber MA. Lyme disease. In: Remington JS, Klein JO,Wilson CB, Baker CJ, eds. Infectious diseases of the fetus and newborninfant, 6th ed. Philadelphia: Elsevier Saunders, 2006:485–97.

51. Gerber MA, Zalneraitis EL. Childhood neurologic disorders and Lymedisease during pregnancy. Pediatr Neurol 1994; 11:41–3.

52. Spielman A, Wilson ML, Levine JF, Piesman J. Ecology of Ixodesdammini–borne human babesiosis and Lyme disease. Annu Rev En-tomol 1985; 30:439–60.

53. Pusterla N, Leutenegger CM, Chae JS, et al. Quantitative evaluationof ehrlichial burden in horses after experimental transmission of hu-man granulocytic Ehrlichia agent by intravenous inoculation withinfected leukocytes and by infected ticks. J Clin Microbiol 1999; 37:4042–4.

54. Wang G, Liveris D, Brei B, et al. Real-time PCR for simultaneousdetection and quantification of Borrelia burgdorferi in field-collectedIxodes scapularis ticks from the northeastern United States. Appl En-viron Microbiol 2003; 69:4561–5.

55. Tsao JI, Wootton JT, Bunikis J, Luna MG, Fish D, Barbour AG. An


ecological approach to preventing human infection: vaccinating wildmouse reservoirs intervenes in the Lyme disease cycle. Proc Nat AcadSci U S A 2004; 101:18159–64.

56. Daniels TJ, Boccia TM, Varde S, et al. Geographic risk for Lyme diseaseand human granulocytic ehrlichiosis in Southern New York State.Appl Environ Microbiol 1998; 64:4663–9.

57. Eisen RJ, Mun J, Eisen L, Lane RS. Life stage–related differences indensity of questing ticks and infection with Borrelia burgdorferi sensulato within a single cohort of Ixodes pacificus (Acari:Ixodidae). J MedEntomol 2004; 41:768–73.

58. Lane RS, Quistad GB. Borreliacidal factor in the blood of the westernfence lizard (Sceloporus occidentalis). J Parasitol 1998; 84:29–34.

59. Ullmann AJ, Lane RS, Kurtenbach K, et al. Bacteriolytic activity ofselected vertebrate sera for Borrelia burgdorferi sensu stricto and Bor-relia bissettii. J Parasitol 2003; 89:1256–7.

60. Piesman J, Clark KL, Dolan MC, Happ CM, Burkot TR. Geographicsurvey of vector ticks (I. scapularis and I. pacificus) for infection withthe Lyme disease spirochete, Borrelia burgdorferi. J Vector Ecol1999; 24:91–8.

61. Clark K. Borrelia species in host-seeking ticks and small mammals inFlorida. J Clin Microbiol 2004; 42:5076–86.

62. Oliver JH Jr, Clark KL, Chandler FW Jr, et al. Isolation, cultivation,and characterization of Borrelia burgdorferi from rodents and ticks inthe Charleston area of South Carolina. J Clin Microbiol 2000; 38:120–4.

63. Piesman J. Ecology of Borrelia burgdorferi sensu lato in North Amer-ica. In: Gray J, Lane RS, Stanek G, eds. Lyme borreliosis: biology,epidemiology, and control. Wallingford, Oxfordshire, UK: CAB In-ternational, 2002:223–49.

64. Dennis D. Rash decisions: Lyme disease, or not? Clin Infect Dis2005; 41:966–8.

65. Wormser GP, Masters E, Nowakowski J, et al. Prospective clinicalevaluation of patients from Missouri and New York with erythemamigrans–like skin lesions. Clin Infect Dis 2005; 41:958–65.

66. James AM, Liveris D, Wormser GP, Schwartz I, Montecalvo MA,Johnson BJB. Borrelia lonestari infection after a bite by an Amblyommaamericanum tick. J Infect Dis 2001; 183:1810–4.

67. Wormser GP, Masters E, Liveris D, et al. Microbiologic evaluation ofpatients from Missouri with erythema migrans. Clin Infect Dis2005; 40:423–8.

68. Sood SK, Salzman MB, Johnson BJB, et al. Duration of tick attachmentas a predictor of the risk of Lyme disease in an area in which Lymedisease is endemic. J Infect Dis 1997; 175:996–9.

69. Falco RC, Fish D, Piesman J. Duration of tick bites in a Lyme dis-ease–endemic area. Am J Epidemiol 1996; 143:187–92.

70. Cook RJ, Sackett DL. Number needed to treat: a clinically usefulmeasure of treatment effect. BMJ 1995; 310:452–4.

71. Schwartz I, Fish D, Daniels TJ. Prevalence of the rickettsial agent ofhuman granulocytic ehrlichiosis in ticks from a hyperendemic focusof Lyme disease. N Engl J Med 1997; 337:49–50.

72. Falco RC, McKenna DF, Daniels TJ, et al. Temporal relation betweenIxodes scapularis abundance and risk for Lyme disease associated witherythema migrans. Am J Epidemiol 1999; 149:771–6.

73. Piesman J, Mather TN, Sinsky RJ, Spielman A. Duration of tick at-tachment and Borrelia burgdorferi transmission. J Clin Microbiol1987; 25:557–8.

74. Piesman J, Maupin GO, Campos EG, Happ CM. Duration of adultfemale Ixodes dammini attachment and transmission of Borrelia burg-dorferi with description of a needle aspiration isolation method. JInfect Dis 1991; 163:895–7.

75. Peavey CA, Lane RS. Transmission of Borrelia burgdorferi by Ixodespacificus nymphs and reservoir competence of deer mice (Peromyscusmaniculatus) infected by tick-bite. J Parasitol 1995; 81:175–8.

76. Ohnishi J, Piesman J, de Silva AM. Antigenic and genetic heteroge-neity of Borrelia burgdorferi populations transmitted by ticks. ProcNatl Acad Sci U S A 2001; 98:670–5.

77. Ribeiro JM, Mather TN, Piesman J, Spielman A. Dissemination andsalivary delivery of Lyme disease spirochetes in vector ticks (Acari:Ixodidae). J Med Entomol 1987; 24:201–5.

78. Kahl O, Janetzki-Mitttman C, Gray JS, Jonas R, Stein J, de Boer R.Risk of infection with Borrelia burgdorferi sensu lato for a host inrelation to the duration of nymphal Ixodes ricinus feeding and themethod of tick removal. Zentralbl Bakteriol 1998; 287:41–52.

79. Crippa M, Rais O, Gern L. Investigations on the mode and dynamicsof transmission and infectivity of Borrelia burgdorferi sensu strictoand Borrelia afzelii in Ixodes ricinus ticks. Vector Borne Zoonotic Dis2002; 2:3–9.

80. Piesman J, Spielman A. Human babesiosis on Nantucket Island: prev-alence of Babesia microti in ticks. Am J Trop Med Hyg 1980; 29:742–6.

81. Das S, Deponte K, Marcantonio NL, et al. Granulocytic ehrlichiosisin tick-immune guinea pigs. Infect Immun 1998; 66:1803–5.

82. Telford SR, Dawson JE, Katavolos P, Warmer CK, Kolbert CP, PersingDH. Perpetuation of the agent of human granulocytic ehrlichiosisdeer tick-rodent cycle. Proc Natl Acad Sci U S A 1996; 93:6209–14.

83. des Vignes F, Piesman J, Heffernan R , Schulze TL, Stafford KC III,Fish D. Effect of tick removal on transmission of Borrelia burgdorferiand Ehrlichia phagocytophila by Ixodes scapularis nymphs. J Infect Dis2001; 183:773–8.

84. Saltzman MB, Rubin LG, Sood SK. Prevention of Lyme disease aftertick bites [letter]. N Engl J Med 1993; 328:137.

85. Nowakowski J, McKenna D, Nadelman RB, Falco RC, Aguero-Ro-senfeld M, Wormser GP. Evaluation of an interactive training programon Lyme disease for health care providers [abstract P-78]. In: Programand abstracts of the 9th International Conference on Lyme Borreliosisand Other Tick-borne Diseases (New York). New York: New YorkMedical College and Imedex, 2003.

86. Falco RC, McKenna D, Nowakowski J, Nadelman R, Wormser GP,Daniels TJ. Evaluation of patient assessment of tick bite duration andeligibility for Lyme disease prophylaxis in a clinical setting [abstractP203]. In: Programs and abstracts of the 10th International Confer-ence on Lyme Borreliosis and Other Tick-borne Diseases (Vienna,Austria). Austrian Society for Hygeine, Microbiology, and PreventiveMedicine, 2005:120.

87. Gerber MA, Shapiro Ed, Burke GS, et al. Lyme disease in children insoutheastern Connecticut. N Engl J Med 1996; 335:1270–4.

88. Wormser GP, McKenna D, Nadelman RB, Nowakowski J, WeinsteinA. Lyme disease in children [letter]. N Engl J Med 1997; 336:1107.

89. Sigal LH, Zahradnik JM, Lavin P, et al. A vaccine consisting of re-combinant Borrelia burgdorferi outer-surface protein A to preventLyme disease. N Engl J Med 1998; 339:216–22.

90. Berger BW. Dermatologic manifestations of Lyme disease. Rev InfectDis 1989; 11(Suppl 6):S1475–81.

91. Nadelman RB, Nowakowski J, Forseter G, et al. The clinical spectrumof early Lyme borreliosis in patients with culture positive erythemamigrans. Am J Med 1996; 100:502–8.

92. Melski JW, Reed KD, Mitchell PD, Barth GD. Primary and secondaryerythema migrans in central Wisconsin. Arch Dermatol 1993; 129:709–16.

93. Steere AC, Bartenhagen NH, Craft JE, et al. The early clinical man-ifestations of Lyme disease. Ann Intern Med 1983; 99:76–82.

94. Bakken JS, Krueth J, Wilson-Nordskog C, Tilden RL, Asanovich K,Dumler JS. Clinical and laboratory characteristics of human granu-locytic ehrlichiosis. JAMA 1996; 275:199–205.

95. Aguero-Rosenfeld ME, Horowitz HW, Wormser GP, et al. Humangranulocytic ehrlichiosis: a case series from a single medical center inNew York State. Ann Intern Med 1996; 125:904–8.

96. White DJ, Talarico J, Chang H-G, Birkhead GS, Heimberger T, MorseDL. Human babesiosis in New York State: review of 139 hospitalizedcases and analysis of prognostic factors. Arch Intern Med 1998; 158:2149–54.

97. Steere AC, Sikand VK, Schoen RT, Nowakowski J. Asymptomaticinfection with Borrelia burgdorferi. Clin Infect Dis 2003; 37:528–32.


98. Brown SL, Hansen SL, Langone JJ. Role of serology in the diagnosisof Lyme disease. JAMA 1999; 282:62–6.

99. Wormser GP, Aguero-Rosenfeld ME, Nadelman RB. Lyme diseaseserology: problems and opportunities. JAMA 1999; 282:79–80.

100. Aguero-Rosenfeld ME, Roberge J, Carbonaro CA, Nowakowski J, Na-delman RB, Wormser GP. Effects of Osp A vaccination on Lymedisease serologic testing. J Clin Microbiol 1999; 37:3718–21.

101. American College of Physicians. Guidelines for laboratory evaluationin the diagnosis of Lyme disease. Ann Intern Med 1997; 127:1106–8.

102. Tugwell P, Dennis DT, Weinstein A, et al. Clinical guideline, part 2:laboratory evaluation in the diagnosis of Lyme disease. Ann InternMed 1997; 127:1109–23.

103. Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosisof Lyme borreliosis. Clin Microbiol Rev 2005; 18:484–509.

104. Seltzer EG, Shapiro ED. Misdiagnosis of Lyme disease: when not toorder serologic tests. Pediatr Infect Dis J 1996; 15:762–3.

105. Poland GA, Jacobson RM. The prevention of Lyme disease with vac-cine. Vaccine 2001; 19:2303–8.

106. Nadelman RB, Wormser GP. Erythema migrans and early Lyme dis-ease. Am J Med 1995; 98(Suppl 4A):15S–24S.

107. Steere AC. Lyme disease. N Engl J Med 1989; 321:586–96.108. Nadelman RB, Wormser GP. Lyme borreliosis. Lancet 1998; 352:

557–65.109. Stanek G, Strle F. Lyme borreliosis. Lancet 2003; 362:1639–47.110. Smith RP, Schoen RT, Rahn DW, et al. Clinical characteristics and

treatment outcome of early Lyme disease in patients with microbi-ologically confirmed erythema migrans. Ann Intern Med 2002; 136:421–8.

111. Steere AC. Lyme disease. N Engl J Med 2001; 345:115–25.112. Centers for Disease Control and Prevention. Case definitions for in-

fectious conditions under public health surveillance: Lyme disease(revised 9/96). MMWR Morb Mortal Wkly Rep 1997; 46(RR-10):1–51.

113. Wormser GP, McKenna D, Carlin J, et al. Brief communication: he-matogenous dissemination in early Lyme disease. Ann Intern Med2005; 142:751–5.

114. Wormser GP. Clinical practice: early Lyme disease. N Engl J Med2006; 354:2794–801.

115. Goldberg NS, Forseter G, Nadelman RB, et al. Vesicular erythemamigrans. Arch Dermatol 1992; 128:1495–8.

116. Nowakowski J, Schwartz I, Liveris D, et al. Laboratory diagnostictechniques for patients with early Lyme disease associated with ery-thema migrans: a comparison of different techniques. Clin Infect Dis2001; 33:2023–7.

117. Centers for Disease Control and Prevention. Recommendations fortest performance and interpretation from the Second National Con-ference on Serologic Diagnosis of Lyme Disease. MMWR Morb MortalWkly Rep 1995; 44:590–1.

118. Centers for Disease Control and Prevention. Notice to readers: cautionregarding testing for Lyme disease. MMWR Morb Mortal Wkly Rep2005; 54:125–6.

119. Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretationcriteria for serodiagnosis of early Lyme disease. J Clin Microbiol1995; 33:419–27.

120. Dressler F, Whalen JA, Reinhardt BN, Steere AC. Western blotting inthe serodiagnosis of Lyme disease. J Infect Dis 1993; 167:392–400.

121. Johnson BJ, Robbins KE, Bailey RE, et al. Serodiagnosis of Lymedisease: accuracy of a two-step approach using flagella-based ELISAand immunoblotting. J Infect Dis 1996; 174:346–53.

122. Hilton E, DeVoti J, Benach JL, et al. Seroprevalence and seroconver-sion for tick-borne diseases in a high-risk population in the northeastUnited States. Am J Med 1999; 106:404–9.

123. Coulter P, Lema C, Flayhart D, et al. Two-year evaluation of Borreliaburgdorferi culture and supplemental tests for definitive diagnosis ofLyme disease. J Clin Microbiol 2005; 43:5080–4.

124. Dumler JS. Molecular diagnosis of Lyme disease: review and meta-analysis. Mol Diagn 2001; 6:1–11.

125. Agger WA, Callister SM, Jobe DA. In vitro susceptibilities of Borreliaburgdorferi to five oral cephalosporins and ceftriaxone. AntimicrobAgents Chemother 1992; 36:1788–90.

126. Mursic VP, Wilske B, Schierz G, Holmburger M, Sub E. In vitro andin vivo susceptibility of Borrelia burgdorferi. Eur J Clin Microbiol1987; 6:424–6.

127. Johnson SE, Klein GC, Schmid GP, Feeley JC. Susceptibility of theLyme disease spirochete to seven antimicrobial agents. Yale J Biol Med1984; 57:549–53.

128. Johnson RC, Kodner C, Russell M. In vitro and in vivo susceptibilityof the Lyme disease spirochete, Borrelia burgdorferi, to four antimi-crobial agents. Antimicrob Agents Chemother 1987; 31:164–7.

129. Baradaran-Dilmaghani R, Stanek G. In vitro susceptibility of thirtyBorrelia strains from various sources against eight antimicrobial che-motherapies. Infection 1996; 24:60–3.

130. Dever LL, Jorgensen JH, Barbour AG. In vitro antimicrobial suscep-tibility testing of Borrelia burgdorferi: a microdilution MIC methodand time-killing studies. J Clin Microbiol 1992; 30:2692–7.

131. Levin JM, Nelson JA, Segreti J, Harrison B, Benson CA, Strle F. Invitro susceptibility of Borrelia burgdorferi to 11 antimicrobial agents.Antimicrob Agents Chemother 1993; 37:1444–6.

132. Johnson RC, Kodner CB, Jurkovich PJ, Collins JJ. Comparative invitro and in vivo susceptibilities of the Lyme disease spirochete Borreliaburgdorferi to cefuroxime and other antimicrobial agents. AntimicrobAgents Chemother 1990; 34:2133–6.

133. Nowakowski J, McKenna D, Nadelman RB, et al. Failure of treatmentwith cephalexin for Lyme disease. Arch Fam Med 2000; 9:563–7.

134. Dever LL, Jorgensen JH, Barbour AG. Comparative in vitro activitiesof clarithromycin, azithromycin, and erythromycin against Borreliaburgdorferi. Antimicrob Agents Chemother 1993; 37:1704–6.

135. Terekhovo D, Sartakova ML, Wormser GP, Schwartz I, Cabello FC.Erythromycin resistance in Borrelia burgdorferi. Antimicrob AgentsChemother 2002; 46:3637–40.

136. Hunfeld KP, Wichelhaus TA, Rodel R, Acher G, Brade V, Kraiczy P.Comparison of in vitro activities of ketolides, macrolides, and anazalide against the spirochete Borrelia burgdorferi. Antimicrob AgentsChemother 2004; 48:344–7.

137. Steere AC, Hutchinson GJ, Rahn DW, et al. Treatment of early man-ifestations of Lyme disease. Ann Intern Med 1983; 99:22–6.

138. Nadelman RB, Luger SW, Frank E, et al. Comparison of cefuroximeaxetil and doxycycline in the treatment of early Lyme disease. AnnIntern Med 1992; 117:273–80.

139. Luger SW, Paparone P, Wormser GP, et al. Comparison of cefuroximeaxetil and doxycycline in treatment of patients with early Lyme diseaseassociated with erythema migrans. Antimicrob Agents Chemother1995; 39:661–7.

140. Dattwyler RJ, Luft BJ, Kunkel M, et al. Ceftriaxone compared withdoxycycline for the treatment of acute disseminated Lyme disease. NEngl J Med 1997; 337:289–94.

141. Eppes SC, Childs JA. Comparative study of cefuroxime axetil versusamoxicillin in children with early Lyme disease. Pediatrics 2002; 109:1173–7.

142. Wormser GP, Ramanathan R, Nowakowski J, et al. Duration of an-tibiotic therapy for early Lyme disease: a randomized, double-blind,placebo-controlled trial. Ann Intern Med 2003; 138:697–704.

143. Steere AC, Malawista SE, Newman JH, Spieler PN, Bartenhagen NH.Antibiotic therapy in Lyme disease. Ann Intern Med 1980; 93:1–8.

144. Nowakowski J, Nadelman RB, Forseter G, McKenna D, Wormser GP.Doxycycline versus tetracycline therapy for Lyme disease associatedwith erythema migrans. J Am Acad Dermatol 1995; 32:223–7.

145. Luft B, Steinman CR, Neimark HC, et al. Invasion of the centralnervous system by Borrelia burgdorferi in acute disseminated infection.JAMA 1992; 267:1364–7.

146. Treatment of Lyme disease. Med Lett Drug Ther 2005; 47:41–3.147. Hansen K, Hovmark A, Lebech A-M, et al. Roxithromycin in Lyme

borreliosis: discrepant results of an in vitro and in vivo animal sus-


ceptibility study and a clinical trial in patients with erythema migrans.Acta Derm Venereol 1992; 72:297–300.

148. Dattwyler RJ, Grunwaldt E, Luft BJ. Clarithromycin in treatment ofearly Lyme disease: a pilot study. Antimicrob Agents Chemother1996; 40:468–9.

149. Halperin JJ, Logigian EL, Finkel MF, Pearl RA. Practice parametersfor the diagnosis of patients with nervous system Lyme borreliosis(Lyme disease). Neurology 1996; 46:619–27.

150. Halperin JJ, Pass HL, Anand AK, Luft BJ, Volkman DJ, Dattwyler RJ.Nervous system abnormalities in Lyme disease. Ann N Y Acad Sci1988; 539:24–34.

151. Finkel MJ, Halperin JJ. Nervous system Lyme borreliosis—revisited.Arch Neurol 1992; 49:102–7.

152. Halperin JJ, Luft BJ, Anand AK, Roque CT, Alvarez O, Volkman DJ,Dattwyler RJ. Lyme neuroborreliosis: central nervous system mani-festations. Neurology 1989; 39:753–9.

153. Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme ar-thritis. Ann Intern Med 1987; 107:725–31.

154. Reik L, Steere AC, Bartenhagen NH, Shope RE, Malawista SE. Neu-rologic abnormalities of Lyme disease. Medicine 1979; 58:281–94.

155. Clark JR, Carlson RD, Sasaki CT, Pachies AR, Steere AC. Facial pa-ralysis in Lyme disease. Laryngoscope 1985; 95:1341–5.

156. Shapiro ED, Gerber MA. Lyme disease and facial nerve palsy. ArchPediatr Adolesc Med 1997; 151:1183–4.

157. Halperin JJ, Golightly M. Lyme borreliosis in Bell’s palsy. Long IslandNeuroborreliosis Collaborative Study Group. Neurology 1992; 42:1268–70.

158. Eppes SC, Nelson DK, Lewis LL, Klein JD. Characterization of Lymemeningitis and comparison with viral meningitis in children. Pedi-atrics 1999; 103:957–60.

159. Shah SS, Zaoutis T, Turnquist J, Hodinka RL, Coffin SE. Early dif-ferentiation of Lyme from enteroviral meningitis. Pediatr Infect DisJ 2005; 24:542–5.

160. Rothermel H, Hedges TR III, Steere AC. Optic neuropathy in childrenwith Lyme disease. Pediatrics 2001; 108:477–81.

161. Nord JA, Karter D. Lyme disease complicated with pseudotumor cer-ebri. Clin Infect Dis 2003; 37:e25–6.

162. Bacon RM, Biggerstaff BJ, Schriefer ME, et al. Serodiagnosis of Lymedisease by kinetic enzyme-linked immunosorbent assay using recom-binant VlsE1 or peptide antigens of Borrelia burgdorferi comparedwith 2-tiered testing using whole-cell lysates. J Infect Dis 2003; 187:1187–99.

163. Stiernstedt G, Gustafsson R, Karlsson M, Svenungsson B, SkoldenbergB. Clinical manifestations and diagnosis of neuroborreliosis. Ann NY Acad Sci 1988; 539:46–55.

164. Peltomaa M, McHugh G, Steere AC. The VlsE (IR6) peptide ELISAin the serodiagnosis of Lyme facial paralysis. Otol Neurotol 2004; 25:838–41.

165. Henriksson A, Link H, Cruz M, Stiernstedt G. Immunoglobin ab-normalities in cerebrospinal fluid and blood over the course of lym-phocytic meningoradiculitis (Banwarth’s syndrome). Ann Neurol1986; 20:337–45.

166. Steere AC, Berardi VP, Weeks KE, Logigian EL, Ackerman R. Eval-uation of the intrathecal antibody response to Borrelia burgdorferi asa diagnostic test for Lyme neuroborreliosis. J Infect Dis 1990; 161:1203–9.

167. Nocton JJ, Bloom BJ, Rutledge BJ, et al. Detection of Borrelia burg-dorferi DNA by polymerase chain reaction in cerebrospinal fluid inLyme neuroborreliosis. J Infect Dis 1996; 174:623–7.

168. Halperin JJ, Shapiro E, Logigian E, et al. Practice parameter: treatmentof nervous system Lyme disease. A Report of the Quality StandardsSubcommittee of the American Academy of Neurology (in press).

169. Steere AC, Pachner AR, Malawista SE. Neurologic abnormalities ofLyme disease: successful treatment with high-dose intravenous pen-icillin. Ann Intern Med 1983; 99:767–72.

170. Wormser GP. Treatment and prevention of Lyme disease, with em-

phasis on antimicrobial therapy for neuroborreliosis and vaccination.Semin Neurol 1997; 17:45–52.

171. Pfister HW, Preac-Mursic V, Wilske B, Einhaupl KM. Cefotaxime vs.penicillin G for acute neurologic manifestations in Lyme borreliosis:a prospective randomized study. Arch Neurol 1989; 46:1190–4.

172. Mullegger RR, Millner MM, Stanek G, Spork KD. Penicillin G sodiumand ceftriaxone in the treatment of neuroborreliosis in children—aprospective study. Infection 1991; 19:279–83.

173. Pfister HW, Preac-Mursic V, Wilske B, Schielke E, Sorgel F, EinhauplKM. Randomized comparison of ceftriaxone and cefotaxime in Lymeneuroborreliosis. J Infect Dis 1991; 163:311–8.

174. Dotevall L, Alestig K, Hanner P, Norkrans G, Hagberg L. The use ofdoxycycline in nervous system Borrelia burgdorferi infection. Scand JInfect Dis Suppl 1988; 53:74–9.

175. Dotevall L, Hagberg L. Successful oral doxycycline treatment of Lymedisease–associated facial palsy and meningitis. Clin Infect Dis 1999;28:569–74.

176. Karlsson M, Hammers-Berggren S, Lindquist L, Stiernstedt G, Sven-ungsson B. Comparison of intravenous penicillin G and oral doxy-cycline for treatment of Lyme neuroborreliosis. Neurology 1994; 44:1203–7.

177. Kohlhepp W, Oschmann P, Mertens H-G. Treatment of Lyme bor-reliosis: randomized comparison of doxycycline and penicillin G. JNeurol 1989; 236:464–9.

178. Thorstrand C, Belfrage E, Bennet R, Malmborg P, Eriksson M. Suc-cessful treatment of neuroborreliosis with ten day regimens. PediatrInfect Dis J 2002; 21:1142–5.

179. Borg R, Dotevall L, Hagberg L, et al. Intravenous ceftriaxone com-pared with oral doxycycline for the treatment of Lyme neuroborre-liosis. Scand J Infect Dis 2005; 37:449–54.

180. Karkkonen K, Stiernstedt SH, Karlsson M. Follow-up of patientstreated with oral doxycycline for Lyme borreliosis. Scand J Infect Dis2001; 33:259–62.

181. Kalish RA, Kaplan RF, Taylor E, Jones-Woodward L, Workman K,Steere AC. Evaluation of study patients with Lyme disease, 10–20 yearfollow-up. J Infect Dis 2001; 183:453–60.

182. Steere AC, Batsford WP, Weinberg M, et al. Lyme carditis: cardiacabnormalities of Lyme disease. Ann Intern Med 1980; 93:8–16.

183. Sigal LH. Early disseminated Lyme disease: cardiac manifestations.Am J Med 1995; 98:25S–8S.

184. Van der Linde MR. Lyme carditis: clinical characteristics of 105 cases.Scand J Infect Dis Suppl 1991; 77:81–4.

185. Cox J, Krajden M. Cardiovascular manifestations of Lyme disease.Am Heart J 1991; 122:1449–55.

186. McAlister HF, Klementowicz PT, Andrews C, Fisher JD, Feld M, Fur-man S. Lyme carditis: an important course of reversible heart block.Ann Intern Med 1989; 110:339–45.

187. Pinto DS. Cardiac manifestations of Lyme disease. Med Clin NorthAm 2002; 86:285–96.

188. Haddad FA, Nadelman RB. Lyme disease and the heart. Front Biosci2003; 8:s769–82.

189. Sangha O, Phillips CB, Fleischman KE, et al. Lack of cardiac mani-festations among patients with previously treated Lyme disease. AnnIntern Med 1998; 128:346–53.

190. Sonnesyn SW, Diehl SC, Johnson RC, Kubo SH, Goodman JL. Aprospective study of the seroprevalence of Borrelia burgdorferi infec-tion in patients with severe heart failure. Am J Cardiol 1995; 76:97–100.

191. Rubin DA, Sorbera C, Nikitin P, McAllister A, Wormser GP, NadelmanRB. Prospective evaluation of heart block complicating early Lymedisease. Pace 1992; 15:252–5.

192. van der Linde MR, Ballmer PE. Lyme carditis. In: Weber K, BurgdorferW, eds. Aspects of Lyme borreliosis. Berlin: Springer, 1993:131–51.

193. Strle F, Pleterski-Rigler D, Stanek G, Pejovnik-Pustinek A, Ruzic E,Cimperman J. Solitary borrelial lymphocytoma: report of 36 cases.Infection 1992; 20:201–6.

194. Maraspin V, Cimperman J, Lotric-Furlan S, et al. Solitary borrelial


lymphocytoma in adult patients. Wien Klin Wochenschr 2002; 114:515–23.

195. Muellegger RR. Dermatological manifestations of Lyme borreliosis.Eur J Dermatol 2004; 14:296–309.

196. Colli C, Leinweber B, Mullegger R, Chott A, Kerl H, Cerroni L.Borrelia burgdorferi–associated lymphocytoma cutis: clinicopathol-ogic, immunophenotypic, and molecular study of 106 cases. J CutanPathol 2004; 31:232–40.

197. Asbrink E, Hovmark A. Early and late cutaneous manifestations inIxodes-borne borreliosis (erythema migrans borreliosis, Lyme borre-liosis). Ann N Y Acad Sci 1988; 539:4–15.

198. Weber K, Neubert U. Clinical features of early erythema migrans andrelated disorders. Zentralbl Bakteriol Hyg [A] 1986; 263:209–28.

199. Asbrink E, Hovmark A, Olsson I. Lymphadenosis benigna cutis so-litaria-borrelia lymphocytoma in Sweden. Zentralbl Bakteriol 1989;(Suppl 18):156–63.

200. Strle F, Maraspin V, Pleterski-Rigler D, et al. Treatment of borreliallymphocytoma. Infection 1996; 24:80–4.

201. Moreno C, Kutzner H, Palmedo G, Goerttler E, Carrasco L, RequenaL. Interstitial granulomatous dermatitis with histiocytic pseudoroset-tes: a new histopathologic pattern in cutaneous borreliosis. Detectionof Borrelia burgdorferi DNA sequences by a highly sensitive PCR-ELISA. J Am Acad Dermatol 2003; 48:376–84.

202. Sibony P, Halperin J, Coyle PK, Patel K. Reactive Lyme serology inoptic neuritis. J Neuroophthalmol 2005; 25:71–82.

203. Vazquez M, Cartter MJ, Shapiro ED. Accuracy of reporting of Lymedisease in Connecticut [abstract 1867]. Pediatr Res 2003; 53:327A.

204. Steere AC, Malawista SE, Hardin JA, Ruddy S, Askenase PW, AndimanWA. Erythema chronicum migrans and Lyme arthritis: the enlargingclinical spectrum. Ann Intern Med 1977; 86:685–98.

205. Steere AC, Glickstein L. Elucidation of Lyme arthritis. Nat Rev Im-munol 2004; 4:143–52.

206. Steere AC. Diagnosis and treatment of Lyme arthritis. Med Clin NorthAm 1997; 81:179–94.

207. Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC.Detection of Borrelia burgdorferi by polymerase chain reaction insynovial fluid from patients with Lyme arthritis. N Engl J Med1994; 330:229–34.

208. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestationsof Lyme disease. N Engl J Med 1990; 323:1438–44.

209. Kaplan RF, Jones-Woodward L. Lyme encephalopathy: a neuropsy-chological perspective. Semin Neurol 1997; 17:31–7.

210. Kaplan RF, Meadows ME, Vincent LC, Logigian EL, Steere AC. Mem-ory impairment and depression in patients with Lyme encephalop-athy: comparison with fibromyalgia and non-psychotically depressedpatients. Neurology 1992; 42:1263–7.

211. Halperin JJ, Krupp LB, Golightly MG, Volkman DJ. Lyme borre-liosis–associated encephalopathy. Neurology 1990; 40:1340–3.

212. Kaplan RF, Jones-Woodward L, Workman K, Steere AC, Logigian EL,Meadows M-E. Neuropsychological deficits in Lyme disease patientswith and without other evidence of central nervous system pathology.Applied Neuropsychol 1999; 6:3–11.

213. Ackermann R, Rehse-Kupper B, Gollmer E, Schmidt R. Chronic neu-rologic manifestations of erythema migrans borreliosis. Ann N Y AcadSci 1988; 539:16–23.

214. Hammers-Berggren S, Hansen K, Lebech A-M, Karlsson M. Borreliaburgdorferi specific intrathecal antibody production in neuroborre-liosis: a follow-up study. Neurology 1993; 43:169–75.

215. Kalina P, Decker A, Kornel E, Halperin JJ. Lyme disease of the brain-stem. Neuroradiology 2005; 47:903–7.

216. Coyle PK. Borrelia burgdorferi antibodies in multiple sclerosis patients.Neurology 1989; 39:760–1.

217. Halperin JJ, Volkman DJ, Wu P. Central nervous system abnormalitiesin Lyme neuroborreliosis. Neurology 1991; 41:1571–82.

218. Coyle PK, Krupp LB, Doscher C. Significance of reactive Lyme se-rology in multiple sclerosis. Ann Neurol 1993; 34:745–7.

219. Halperin J, Luft BJ, Volkman DJ, Dattwyler RJ. Lyme neuroborreliosis:peripheral nervous system manifestations. Brain 1990; 113:1207–21.

220. Halperin JJ, Little BW, Coyle PK, Dattwyler RJ. Lyme disease: causeof a treatable peripheral neuropathy. Neurology 1987; 37:1700–6.

221. Vallat JM, Hugon J, Lubeau M, Leboutet MJ, Dumas M, Desproges-Gotteron R. Tick bite meningoradiculoneuritis. Neurology 1987; 37:749–53.

222. Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lymeencephalopathy with intravenous ceftriaxone. J Infect Dis 1999; 180:377–83.

223. Steere AC. A 58-year-old man with a diagnosis of chronic Lymedisease. JAMA 2002; 288:1002–10.

224. Steere AC, Green J, Schoen RT, et al. Successful parenteral penicillintherapy of established Lyme arthritis. N Engl J Med 1985; 312:869–74.

225. Dattwyler RJ, Halperin JJ, Pass H, Luft BJ. Ceftriaxone as effectivetherapy for refractory Lyme disease. J Infect Dis 1987; 155:1322–5.

226. Dattwyler RJ, Halperin JJ, Volkman DJ, Luft BJ. Treatment of lateLyme borreliosis—randomized comparison of ceftriaxone and peni-cillin. Lancet 1988; 1:1191–4.

227. Dattwyler RJ, Wormser GP, Rush TJ, et al. A comparison of twotreatment regimens of ceftriaxone in late Lyme disease. Wien KlinWochenschr 2005; 117:393–7.

228. Eichenfield AH, Goldsmith DP, Benach JL, et al. Childhood Lymearthritis: experience in an endemic area. J Pediatr 1986; 109:753–8.

229. Fishman RA. Blood-brain and CSF barriers to penicillin and relatedorganic acids. Arch Neurol 1966; 15:113–24.

230. Eckman MH, Steere AC, Kalish RA, Pauker SG. Cost effectiveness oforal as compared with intravenous antibiotic treatment for patientswith early Lyme disease or Lyme arthritis. N Engl J Med 1997; 337:357–63.

231. Carlson D, Hernandez J, Bloom BJ, Coburn J, Aversa JM, Steere AC.Lack of Borrelia burgdorferi DNA in synovial samples from patientswith antibiotic treatment-resistant Lyme arthritis. Arthritis Rheum1999; 42:2705–9.

232. Gross DM, Forsthuber T, Tary-Lehmann M, et al. Identification ofLFA-1 as a candidate autoantigen in treatment resistant Lyme arthritis.Science 1998; 281:703–6.

233. Steere AC, Klitz W, Drouin EE, et al. Antibiotic-refractory Lyme ar-thritis is associated with HLA-DR molecules that bind a Borrelia burg-dorferi peptide. J Exp Med 2006; 203:961–71.

234. Jaulhac B, Chary-Valckenaere I, Sibilia J, et al. Detection of Borreliaburgdorferi by DNA amplification in synovial tissue samples frompatients with Lyme arthritis. Arthritis Rheum 1996; 39:736–45.

235. Schoen RT, Aversa JM, Rahn DW, Steere AC. Treatment of refractorychronic Lyme arthritis with arthroscopic synovectomy. ArthritisRheum 1991; 34:1056–60.

236. Malawista SE. Resolution of Lyme arthritis, acute or prolonged: a newlook. Inflammation 2000; 24:493–504.

237. Battafarano DF, Combs JA, Enzenauer RJ, Fitzpatrick JE. Chronicseptic arthritis caused by Borrelia burgdorferi. Clin Orthop Relat Res1993; 297:238–41.

238. Steere AC, Angelis S. Therapy for Lyme arthritis: strategies for thetreatment of antibiotic-refractory arthritis. Arthritis Rheum 2006; 54:3079–85.

239. Bloom BJ, Wyckoff PM, Meissner HC, Steere AC. Neurocognitiveabnormalities in children after classic manifestations of Lyme disease.Pediatric Infect Dis J 1998; 17:189–96.

240. Hassler D, Zoller L, Haude A, Hufnagel H-D, Heinrich F, SonntagH-G. Cefotaxime versus penicillin in the late stage of Lyme disease—prospective, randomized therapeutic approach. Infection 1990; 18:16–9.

241. Ettestad PJ, Campbell GL, Welbel SF, et al. Biliary complications inthe treatment of unsubstantiated Lyme disease. J Infect Dis 1995; 171:356–61.

242. Asbrink E, Hovmark A, Olsson I. Clinical manifestations of acro-dermatitis chronica atrophicans in 50 Swedish patients. Zentralbl Bak-teriol Mikrobiol Hyg A 1986; 263:253–61.


243. Ohlenbush A, Matuscha FR, Richter D, et al. Etiology of acroder-matitis chronica atrophicans lesion in Lyme disease. J Infect Dis1996; 174:421–3.

244. Ruzic-Sabljic E, Maraspin V, Lotric-Furlan S, Cimperman J, Strle F.Characterisation of Borrelia burgdorferi sensu lato strains isolated fromhuman material in Slovenia. Wien Klin Wochenschr 2002; 114:544–50.

245. Lavoie PE, Wilson AJ, Tuffanelli DL. Acrodermatitis chronica atro-phicans with antecedent Lyme disease in a Californian. Zentralbl Bak-teriol Mikrobiol Hyg [A] 1986; 263:262–5.

246. DiCaudo DJ, Su WP, Marshall WF, Malawista SE, Barthold S, PersingDH. Acrodermatitis chronica atrophicans in the United States: clinicaland histopathologic features of six cases. Cutis 1994; 54:81–4.

247. Maraspin V, Ruzic-Sabljic E, Strle F. Isolation of Borrelia burgdorferisensu lato from a fibrous nodule in a patient with acrodermatitischronica atrophicans. Wien Klin Wochenschr 2002; 114:533–4.

248. Kristoferitsch W, Sluga E, Graf M, Partsch H, Neumann R, StanekG, Budka H. Neuropathy associated with acrodermatitis chronicaatrophicans: clinical and morphological features. Ann N Y Acad Sci1988; 539:35–45.

249. Kindstrand E, Nilsson BY, Hovmark A, Pirskanen R, Asbrink E. Pe-ripheral neuropathy in acrodermatitis chronica atrophicans—a lateBorrelia manifestation. Acta Neurol Scand 1997; 95:338–45.

250. Strle F. Principles of the diagnosis and antibiotic treatment of Lymeborreliosis. Wien Klin Wochenschr 1999; 111:911–5.

251. Weber K. Therapy of cutaneous manifestations. In: Weber K, Burg-dorfer W, Schierz G, eds. Aspects of Lyme borreliosis. Berlin, Hei-delberg, New York: Springer-Verlag, 1993:312–27.

252. Kindstrand E, Nilsson BY, Hovmark A, Pirskanen R, Asbrink E. Pe-ripheral neuropathy in acrodermatitis chronica atrophicans—effect oftreatment. Acta Neurol Scand 2002; 106:253–7.

253. Reid MC, Schoen RT, Evans J, Rosenberg JC, Horwitz RI. The con-sequences of overdiagnosis and overtreatment of Lyme disease: anobservational study. Ann Intern Med 1998; 128:354–362.

254. Patel R, Grogg KL, Edwards WD, Wright AJ, Schwenk NM. Deathfrom inappropriate therapy for Lyme disease. Clin Infect Dis 2000;31:1107–9.

255. Levy SB, Marshall B. Antibacterial resistance worldwide: causes, chal-lenges and responses. Nat Med 2004; 10:S122–9.

256. Steere AC. Duration of antibiotic therapy for Lyme disease. Ann InternMed 2003; 138:761–2.

257. Nowakowski J, Nadelman RB, Sell R, et al. Long-term follow-up ofpatients with culture-confirmed Lyme disease. Am J Med 2003; 115:91–6.

258. Wang TJ, Liang MH, Sangha O, et al. Coexposure to Borrelia burg-dorferi and Babesia microti does not worsen the long-term outcomeof Lyme disease. Clin Infect Dis 2000; 31:1149–54.

259. Ramsey AH, Belongia EA, Gale CM, Davis JP. Outcomes of treatedhuman granulocytic ehrlichiosis cases. Emerg Infect Dis 2002; 8:398–401.

260. Halperin JJ, Wormser GP. Of fleas and ticks on cats and mice. …Arch Neurol 2001; 58:1345–7.

261. Buchwald D, Umali P, Umali J, Kith P, Pearlman T, Komaroff AL.Chronic fatigue and the chronic fatigue syndrome: prevalence in aPacific Northwest Health Care System. Ann Intern Med 1995; 123:81–8.

262. Chen MK. The epidemiology of self-perceived fatigue among adults.Prev Med 1986; 15:74–81.

263. Wessely S. Chronic fatigue: symptoms and syndrome. Ann Intern Med2001; 134:838–43.

264. Centers for Disease Control and Prevention. Monitoring progress inarthritis management—United States and 25 states, 2003. MMWRMorb Mortal Wkly Rep 2005; 54:484–8.

265. Croft P, Rigby AS, Boswell R, Schollum J, Silman A. The prevalenceof chronic widespread pain in the general population. J Rheumatol1993; 20:710–3.

266. Luo N, Johnson JA, Shaw JW, Feeny D, Coons SJ. Self-reported health

status of the general adult US population as assessed by the EQ-5Dand Health Utilities Index. Med Care 2005; 43:1078–86.

267. Zahran HS, Kobau R, Moriarty DG, et al. Health-related quality oflife surveillance—United States, 1993–2002. MMWR Surveill Summ2005; 54:1–35.

268. Sigal LH, Patella SJ. Lyme arthritis as the incorrect diagnosis in pe-diatric and adolescent fibromyalgia. Pediatrics 1992; 90:523–8.

269. Dinerman H, Steere AC. Lyme disease associated with fibromyalgia.Ann Intern Med 1992; 117:281–5.

270. Lightfoot RW Jr, Luft BJ, Rahn DW, et al. Empiric parenteral antibiotictreatment of patients with fibromyalgia and fatigue and a positiveserologic result for Lyme disease: a cost-effectiveness analysis. AnnIntern Med 1993; 119:503–9.

271. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalenceand characteristics of fibromyalgia in the general population. ArthritisRheum 1995; 38:19–28.

272. Cairns V, Godwin J. Post-Lyme borreliosis syndrome: a meta-analysisof reported symptoms. Int J Epidemiol 2005; 34:1340–5.

273. Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED.Long-term outcomes of persons with Lyme disease. JAMA 2000; 283:609–16.

274. Shadick NA, Phillips CB, Logigian EL, et al. The long-term clinicaloutcomes of Lyme disease: a population-based retrospective cohortstudy. Ann Intern Med 1994; 121:560–7.

275. Shadick NA, Phillips CB, Sangha O, et al. Musculoskeletal and neu-rologic outcomes in patients with previously treated Lyme disease.Ann Intern Med 1999; 131:919–26.

276. Vazquez M, Sparrow SS, Shapiro ED. Long-term neuropsychologicand health outcomes of children with facial nerve palsy attributableto Lyme disease. Pediatrics 2003; 112:e93–7.

277. Wang TJ, Sangha O, Phillips CB, et al. Outcomes of children treatedfor Lyme disease. J Rheumatol 1998; 25:2249–53.

278. Salazar JC, Gerber MA, Goff CW. Long-term outcome of Lyme diseasein children given early treatment. J Pediatr 1993; 122:591–3.

279. Shapiro ED, Dattwyler R, Nadelman RB, Wormser GP. Response tometa-analysis. Int J Epidemiol 2005; 34:1437–9.

280. Shapiro ED. Long-term outcomes of persons with Lyme disease. Vec-tor Borne Zoonotic Dis 2002; 2:279–88.

281. Imboden JB, Canter A, Cluff LE. Convalescence from influenza. ArchIntern Med 1961; 108:115–21.

282. Imboden JR, Canter A, Cluff LE, Trever R. Brucellosis. III. Psychologicaspects of delayed convalescence. Arch Intern Med 1959; 103:406–14.

283. Solomon SP, Hilton E, Weinchel BS, Pollack S, Grolnick E. Psycho-logical factors in the prediction of Lyme disease course. Arthritis CareRes 1998; 11:419–26.

284. Steiner I. Treating post-Lyme disease: trying to solve one equationwith too many unknowns. Neurology 2003; 60:1888–9.

285. Radolf J. Post-treatment chronic Lyme disease: what it is not? J InfectDis 2005; 192:948–9.

286. Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A. Lyme disease:an infectious and post-infectious syndrome. J Rheumatol 1994; 21:454–61.

287. Sigal LH. Misconceptions about Lyme disease: confusions hiding be-hind ill-chosen terminology. Ann Intern Med 2002; 136:413–9.

288. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotictreatment in patients with persistent symptoms and a history of Lymedisease. N Engl J Med 2001; 345:85–92.

289. Klempner MS. Controlled trials of antibiotic treatment in patientswith post-treatment chronic Lyme disease. Vector Borne Zoonotic Dis2002; 2:255–63.

290. Kaplan RF, Trevino RP, Johnson GP, et al. Cognitive function in post-treatment Lyme disease: do additional antibiotics help? Neurology2003; 60:1916–22.

291. Ravdin LD, Hilton E, Primeau M, Clements C, Barr WB. Memoryfunctioning in Lyme borreliosis. J Clin Psychiatry 1996; 57:282–6.

292. Gaudino E, Coyle PK, Krupp LB. Post-Lyme syndrome and chronicfatigue syndrome. Arch Neurol 1997; 54:1372–6.


293. Elkins LE, Pollina DA, Scheffer SR, Krupp LB. Psychological statesand neuropsychological performances in chronic Lyme disease. ApplNeuropsychol 1999; 6:19–26.

294. Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of postLyme disease (stop-LD): a randomized double-masked clinical trial.Neurology 2003; 60:1923–30.

295. Steere AC, Taylor E, McHugh GL, Logigian EL. The over diagnosisof Lyme disease. JAMA 1993; 269:1812–26.

296. Rose CD, Fawcett PT, Gibney KM, Doughty RA. The over diagnosisof Lyme disease in children residing in an endemic area. Clin Pediatr(Phila) 1994; 33:663–8.

297. Sigal LH. The first one hundred patients seen at a Lyme disease referralcenter. Am J Med 1990; 88:577–81.

298. Burdge DR, O’Hanlon DP. Experience of a referral center for patientswith suspected Lyme disease in an area of non-endemicity: first 65patients. Clin Infect Dis 1993; 16:558–60.

299. Nieman GF, Zerler BR. A role for the anti-inflammatory propertiesof tetracyclines in the prevention of acute lung injury. Curr MedChem 2001; 8:317–25.

300. Labro MT. Anti-inflammatory activity of macrolides: a new thera-peutic potential? J Antimicrob Chemother 1998; 41(Suppl B):37–46.

301. Nadelman RB, Nowakowski J, Forseter G, et al. Failure to isolateBorrelia burgdorferi after antimicrobial therapy in culture-documentedLyme borreliosis associated with erythema migrans: report of a pro-spective study. Am J Med 1993; 94:583–8.

302. Berger BW, Johnson RC, Kodner C, Coleman L. Failure of Borreliaburgdorferi to survive in the skin of patients with antibiotic-treatedLyme disease. J Am Acad Dermatol 1992; 27:34–7.

303. Phillips SE, Mattman LH, Hulinska D, Moayad H. A proposal forthe reliable culture of Borrelia burgdorferi from patients with chronicLyme disease, even from those previously aggressively treated. Infec-tion 1998; 26:364–7.

304. Greene RT, Walker RL, Greene CE. Pseudospirochetes in animal bloodbeing cultured for Borrelia burgdorferi. J Vet Diagn Invest 1991; 3:350–2.

305. Marques AR, Stock F, Gill V. Evaluation of a new culture mediumfor Borrelia burgdorferi. J Clin Microbiol 2000; 38:4239–41.

306. Bayer ME, Zhang L, Bayer MH. Borrelia burgdorferi DNA in the urineof treated patients with chronic Lyme disease symptoms: a PCR studyof 97 cases. Infection 1996; 24:347–53.

307. Rauter C, Mueller M, Diterich I, et al. Critical evaluation of urine-based PCR assay for diagnosis of Lyme borreliosis. Clin Diag LabImmunol 2005; 12:910–2.

308. Preac-Mursic V, Weber K, Pfister HW, et al. Survival of Borrelia burg-dorferi in antibiotically treated patients with Lyme borreliosis. Infec-tion 1989; 17:355–9.

309. Preac-Mursic V, Pfister HW, Spiegel H, et al. First isolation of Borreliaburgdorferi from an iris biopsy. J Clin Neuroophthalmol 1993; 13:155–61.

310. Hunfeld KP, Ruzic-Sabljic E, Norris DE, Kraiczy P, Strle F. In vitrosusceptibility testing of Borrelia burgdorferi sensu lato isolates culturedfrom patients with erythema migrans before and after antimicrobialchemotherapy. Antimicrob Agents Chemother 2005; 49:1294–301.

311. Liveris D, Varde S, Iyer R, et al. Genetic diversity of Borrelia burgdorferiin Lyme disease patients as determined by culture versus direct PCRwith clinical specimens. J Clin Microbiol 1999; 37:565–9.

312. Misonne M-C, Van Impe G, Hoet PP. Genetic heterogeneity of Borreliaburgdorferi sensu lato in Ixodes ricinus ticks collected in Belgium. JClin Microbiol 1998; 36:3352–4.

313. Ruzic-Sabljic ER, Podreka T, Maraspin V, Strle F. Susceptibility ofBorrelia afzelii strains to antimicrobial agents. Int J Antimicrob Agents2005; 25:474–8.

314. Yan JJ, Jou R, Ko WC, Wu JJ, Yang ML, Chen HM. The use of variable-number tandem-repeat mycobacterial interspersed repetitive unit typ-ing to identify laboratory cross-contamination with Mycobacteriumtuberculosis. Diagn Microbiol Infect Dis 2005; 52:21–8.

315. Wormser GP. Lyme disease: insights into the use of antimicrobials for

prevention and treatment in the context of experience with otherspirochetal infections. Mt Sinai J Med 1995; 62:188–95.

316. Edwards CN, Nicholson GD, Hassell TA, Everard COR, Callender J.Penicillin therapy in icteric leptospirosis. Am J Trop Med Hyg 1988;39:388–90.

317. Watt G, Padre LP, Tuazon ML, et al. Placebo-controlled trial of in-travenous penicillin for severe and late leptosirosis. Lancet 1988; 1:433–5.

318. Fallon BA, Tager F, Fein L, et al. Repeated antibiotic treatment inchronic Lyme disease. J Spirochetal Tick-Borne Dis 1999; 5:94–102.

319. Centers for Disease Control and Prevention. Sexually transmitted dis-ease treatment guideline. MMWR Morb Mortal Wkly Rep 2002; 51:18–30.

320. Alban PS, Johnson PW, Nelson DR. Serum-starvation-inducedchanges in protein synthesis and morphology of Borrelia burgdorferi.Microbiology 2000; 146:119–27.

321. Kazragis RJ, Dever LL, Jorgensen JH, Barbour AG. In vivo activitiesof ceftriaxone and vancomycin against Borrelia spp. in the mousebrain and other sites. Antimicrob Agents Chemother 1996; 40:2632–6.

322. Pavia C, Inchiosa MA Jr, Wormser GP. Efficacy of short-course cef-triaxone therapy for Borrelia burgdorferi infection in C3H mice. An-timicrob Agents Chemother 2002; 46:132–4.

323. Moody KD, Adams RL, Barthold SW. Effectiveness of antimicrobialtreatment against Borrelia burgdorferi infection in mice. AntimicrobAgents Chemother 1994; 38:1567–72.

324. Malawista SE, Barthold SW, Persing DH. Fate of Borrelia burgdorferiDNA in tissues of infected mice after antibiotic treatment. J InfectDis 1994; 170:1312–6.

325. Bockenstedt LK, Mao J, Hodzic E, Barthold SW, Fish D. Detectionof attenuated, non-infectious spirochetes in Borrelia burgdorferi-in-fected mice after antibiotic treatment. J Infect Dis 2002; 186:1430–7.

326. Straubinger RK, Summers BA, Chang Y-F, Appel MJG. Persistence ofBorrelia burgdorferi in experimentally infected dogs after antibiotictreatment. J Clin Microbiol 1997; 35:111–6.

327. Straubinger RK, Straubinger AF, Summers BA, Jacobson RN. Statusof Borrelia burgdorferi infection after antibiotic treatment and effectsof corticosteroids: an experimental study. J Infect Dis 2000; 181:1069–81.

328. Luft BJ, Volkman DJ, Halperin JJ, Dattwyler RJ. New chemothera-peutic approaches in the treatment of Lyme borreliosis. Ann N YAcad Sci 1988; 539:352–61.

329. Preac-Mursic V, Marget W, Busch U, Pleterski Rigler D, Hagl S. Killkinetics of Borrelia burgdorferi and bacterial findings in relation tothe treatment of Lyme borreliosis. Infection 1996; 24:9–16.

330. Priem S, Klimberg T, Franz J, et al. Comparison of reculture and PCRfor the detection of Borrelia burgdorferi in cell and tissue culturesafter antibiotic treatment. Arthritis Rheum 2001; 44:S1766.

331. Varde S, Wormser GP, Nowakowski J, et al. Lyme disease: disparitybetween culture and polymerase chain reaction detection of Borreliaburgdorferi after exposure to ceftriaxone in vitro. Conn Med 1999;63:589–91.

332. Fallon BA, Sackheim HA, Keilp J, et al. Double-blind placebo-con-trolled retreatment with IV ceftriaxone for Lyme encephalopathy:clinical outcome [abstract 196]. In: Program and abstracts of the 10thInternational Conference on Lyme Borreliosis and Other Tick-BorneDiseases (Vienna, Austria). Austrian Society for Hygeine, Microbi-ology, and Preventive Medicine, 2005:116.

333. Donta ST. Macrolide therapy of chronic Lyme disease. Med Sci Monit2003; 9:PI136–42.

334. Donta ST. Tetracycline therapy of chronic Lyme disease. Clin InfectDis 1997; 25:S52–6.

335. Barthold SW, de Souza MS, Janotka JL, Smith AL, Persing DH.Chronic Lyme borreliosis in the laboratory mouse. Am J Pathol1993; 143:419–20.

336. Craig-Mulius K, Weber GF, Coburn J, Glickstein L. Borrelia burg-dorferi, an extracellular pathogen, circumvents osteopontin in induc-ing an inflammatory cytokine response. J Leukoc Biol 2005; 77:710–8.


337. Klempner MS, Schmid CH, Hu L, et al. Intralaboratory reliability ofserologic and urine testing for Lyme disease. Am J Med 2001; 110:217–9.

338. Dumler JS, Choi K-S, Garcia-Garcia JC, et al. Human granulocyticanaplasmosis and Anaplasma phagocytophilum. Emerg Infect Dis2005; 11:1828–33.

339. Dumler JS, Barbet AF, Bekker CP, et al. Reorganization of genera inthe families Rickettsiaceae and Anaplasmataceae in the order Rick-ettsiales: unification of some species of Ehrlichia with Anaplasma,Cowdria with Ehrlichia and Ehrlichia with Neorickettsia, descriptionsof six new species combinations and designation of Ehrlichia equi and‘HGE agent’ as subjective synonyms of Ehrlichia phagocytophila. IntJ Syst Evol Microbiol 2001; 51:2145–65.

340. Bakken JS, Dumler JS. Human granulocytic ehrlichiosis. Clin InfectDis 2000; 31:554–60.

341. Blanco JR, Oteo JA. Human granulocytic ehrlichiosis in Europe. ClinMicrobiol Infect 2002; 8:763–72.

342. Bakken JS, Dumler JS, Chen SM, Eckman MR, Van Etta LL, WalkerDH. Human granulocytic ehrlichiosis in the upper Midwest UnitedStates: a new species emerging? JAMA 1994; 272:212–8.

343. Wallace BJ, Brady G, Ackman DM, et al. Human granulocytic ehr-lichiosis in New York. Arch Intern Med 1998; 158:769–73.

344. Chapman AS, Bakken JS, Folk SM, et al. Diagnosis and managementof tickborne rickettsial diseases: Rocky Mountain spotted fever, ehr-lichioses, and anaplasmosis—United States. A practical guide for phy-sicians and other health-care professionals. MMWR Recomm Rep2006; 55(RR-4):1–27.

345. Dumler JS, Walker DH. Tick-borne ehrlichioses: more of them, higherincidences, and greater clinical diversity. Lancet Infect Dis 2001; 1:21–8 (preview edition).

346. Olano JP, Walker DH. Human ehrlichioses. Med Clin North Am2002; 86:375–92.

347. Bakken JS, Aguero-Rosenfeld ME, Tilden RL, et al. Serial measure-ments of hematologic counts during the active phase of human gran-ulocytic ehrlichiosis. Clin Infect Dis 2001; 32:862–70.

348. Bakken JS, Haller I, Riddell D, Walls JJ, Dumler JS. The serologicalresponse of patients infected with the agent of human granulocyticehrlichiosis. Clin Infect Dis 2002; 34:22–7.

349. Aguero-Rosenfeld ME. Diagnosis of human granulocytic ehrlichiosis:state of the art. Vector Borne Zoonotic Dis 2002; 2:233–9.

350. Belongia EA, Reed KD, Mitchell PD, et al. Tickborne infections as acause of nonspecific febrile illness in Wisconsin. Clin Infect Dis2001; 32:1434–9.

351. Bakken JS, Dumler JS. Ehrlichia and Anaplasma species. In: Yu V,Weber R, Raoult D, eds. Antimicrobial therapy and vaccine, 2nd ed.New York: Apple Trees Productions, 2002:875–82.

352. Horowitz HW, Hsieh TC, Aguero-Rosenfeld ME, et al. Antimicrobialsusceptibility of Ehrlichia phagocytophila. Antimicrob Agents Che-mother 2001; 45:786–8.

353. Klein MB, Nelson CM, Goodman JL. Antibiotic susceptibility of thenewly cultivated agent of human granulocytic ehrlichiosis: promisingactivity of quinolones and rifamycins. Antimicrob Agents Chemother1997; 41:76–9.

354. Maurin M, Bakken JS, Dumler JS. Antibiotic susceptibilities of An-aplasma (Ehrlichia) phagocytophilum strains from various geographicareas in the United States. Antimicrob Agents Chemother 2003; 47:413–5.

355. Casau NC, Hewins ME, Zaleznik DF. Treatment of human granu-locytic ehrlichiosis during pregnancy and risk of perinatal transmis-sion. Scand J Infect Dis 2002; 34:853–5.

356. Edlow JA. Perinatal transmission of human granulocytic ehrlichiosis.N Engl J Med 1998; 339:1942–3.

357. Horowitz HW, Kilchevsky E, Haber S, et al. Perinatal transmissionof the agent of human granulocytic ehrlichiosis. N Engl J Med1998; 339:375–8.

358. Krause PJ, Corrow CL, Bakken JS. Successful treatment of human

granulocytic ehrlichiosis in children using rifampin. Pediatrics2003; 112:e252–3.

359. Moss WJ, Dumler JS. Simultaneous infection with Borrelia burgdorferiand human granulocytic ehrlichiosis. Pediatr Infect Dis J 2003; 22:91–2.

360. Schiffman J, Haq M, Procopio F, Forman EN. Ehrlichiosis infectionin a 5-year-old boy with neutropenia, anemia, thrombocytopenia, andhepatosplenomegaly. J Pediatr Hematol Oncol 2001; 23:324–7.

361. Ehrlichiosis. In: Pickering LK, ed. Red book, 25th ed. Elk GroveVillage, IL: American Academy of Pediatrics, 2000:234–6.

362. Buitrago MI, Ijdo JW, Rinaudo P, et al. Human granulocytic ehrli-chiosis during pregnancy treated successfully with rifampin. Clin In-fect Dis 1998; 27:213–5.

363. Elston DM. Perinatal transmission of human granulocytic ehrlichiosis.N Engl J Med 1998; 339:1941–2.

364. Ehrlichia and Anaplasma infections (human ehrlichioses). In: Pick-ering LK, ed. Red book: 2006 report of the Committee of InfectiousDiseases, 27th ed. Elk Grove Village, IL: American Academy of Pe-diatrics, 2006:281–4.

365. Lochary ME, Lockhart PB, Williams WT Jr. Doxycycline and stainingof permanent teeth. Pediatr Infect Dis J 1998; 17:429–31.

366. Wormser GP, Filozov A, Telford SR III, et al. Dissociation betweeninhibition and killing by levofloxacin in human granulocytic ana-plasmosis. Vector Borne Zoonotic Dis (in press).

367. Madigan JE, Gribble D. Equine ehrlichiosis in northern California:49 cases (1968–1981). J Am Vet Med Assoc 1987; 190:445–8.

368. Krause PJ. Babesiosis. Med Clin North Am 2002; 86:361–73.369. Spielman A, Clifford, CM, Piesman J, et al. Human babesiosis on

Nantucket Island, USA: description of the vector, Ixodes (Ixodes) dam-mini, n. sp. (Acarina: Ixodidae). J Med Entomol 1979; 15:218–34.

370. Homer MJ, Aguilar-Delfin I, Telford SR, Krause PJ, Persing DH.Babesiosis. Clin Microbiol Rev 2000; 13:451–69.

371. Steketee RW, Eckman MR, Burgess EC, et al. Babesiosis in Wisconsin:a new focus of disease transmission. JAMA 1985; 253:2675–8.

372. Krause PJ, McKay K, Gadbaw J, et al. Increasing health burden ofhuman babesiosis in endemic sites. Am J Trop Med Hyg 2003; 68:431–6.

373. Herwaldt BL, Persing DH, Precigout EA, et al. A fatal case of babesiosisin Missouri: identification of another piroplasm that infects humans.Ann Intern Med 1996; 124:643–50.

374. Persing D, Herwaldt BL, Glaser C, et al. Infection with a babesia-likeorganism in the western United States. N Engl J Med 1995; 332:298–303.

375. Garnham PCC. Human babesiosis: European aspects. Trans R SocTrop Med Hyg 1980; 74:153–5.

376. Gorenflot A, Moubri K, Precigout E, Carcy B, Schetters TP. Humanbabesiosis. Ann Trop Med Parasitol 1998; 92:489–501.

377. Wei Q, Tsuji M, Zamoto A, et al. Human babesiosis in Japan: isolationof Babesia microti–like parasites from an asymptomatic transfusiondonor and from a rodent from an area where babesiosis is endemic.J Clin Microbiol 2001; 39:2178–83.

378. Shih CM, Liu LP, Chung WC, Ong SJ, Wan CC. Human babesiosisin Taiwan: asymptomatic infection with a Babesia microti–like organ-ism in a Taiwanese woman. J Clin Microbiol 1997; 35:450–4.

379. Rios L, Alvarez G, Blair S. Serological and parasitological study andreport of the first case of human babesiosis in Colombia. Revista DaSociedade Brasileira de Medicina Tropical 2003; 36:493–8.

380. Ruebush TK 2nd, Cassaday PB, Marsh HJ, et al. Human babesiosison Nantucket Island: clinical features. Ann Intern Med 1977; 86:6–9.

381. Hatcher JC, Greenberg PD, Antique J, et al. Severe babesiosis in LongIsland: review of 34 cases and their complications. Clin Infect Dis2001; 32:1117–25.

382. Falagas ME, Klempner MS. Babesiosis in patients with AIDS: a chronicinfection presenting as fever of unknown origin. Clin Infect Dis1996; 22:809–12.

383. Rosner F, Zarrabi MH, Benach JL, et al. Babesiosis in splenectomizedadults: review of 22 reported cases. Am J Med 1984; 76:696–701.


384. Ruebush TK 2nd, Juranek DD, Chisholm ES, et al. Human babesiosison Nantucket Island: evidence for self-limited and subclinical infec-tions. N Engl J Med 1977; 297:825–7.

385. Krause PJ, Telford SR, Ryan R, et al. Geographical and temporaldistribution of babesial infection in Connecticut. J Clin Microbiol1991; 29:1–4.

386. Krause PJ, Telford SR, Pollack RJ, et al. Babesiosis: an underdiagnoseddisease of children. Pediatrics 1992; 89:1045–8.

387. Krause PJ, Spielman A, Telford S, et al. Persistent parasitemia fol-lowing acute babesiosis. N Engl J Med 1998; 339:160–5.

388. McQuiston JH, Childs JE, Chamberland ME, et al. Transmission oftickborne agents by blood transfusions: a review of known and po-tential risks in the United States. Transfusion 2000; 40:274–84.

389. Healy GR, Ruebush TK. Morphology of Babesia microti in humanblood smears. Am J Clin Pathol 1980; 73:107–9.

390. Krause PJ, Telford S, Ryan R, et al. Diagnosis of babesiosis: evaluationof a serologic test for the detection of Babesia microti antibody. JInfect Dis 1994; 169:923–6.

391. Krause PJ, Ryan R, Telford S, et al. Efficacy of an IgM serodiagnostictest for the rapid diagnosis of acute babesiosis. J Clin Microbiol1996; 34:2014–6.

392. Persing DH, Mathiesen D, Marshall WF, et al. Detection of Babesiamicroti by polymerase chain reaction. J Clin Microbiol 1992; 30:2097–103.

393. Krause PJ, Telford SR, Spielman A, et al. Comparison of PCR withblood smear and inoculation of small animals for diagnosis of Babesiamicroti parasitemia. J Clin Microbiol 1996; 34:2791–4.

394. Wittner M, Rowin KS, Tanowitz HB, et al. Successful chemotherapyof transfusion babesiosis. Ann Intern Med 1982; 96:601–4.

395. Centers for Disease Control. Clindamycin and quinine treatment forBabesia microti infections. MMWR Morb Mortal Wkly Rep 1983; 32:65–72.

396. Krause PJ, Lepore T, Sikand VJ, et al. Atovaquone and azithromycinfor the treatment of human babesiosis. N Engl J Med 2000; 343:1454–8.

397. Smith RP, Evans AT, Popovsky M, et al. Transfusion-acquired babe-siosis and failure of antibiotic treatment. JAMA 1986; 256:2726–7.

398. Bonoan JT, Johnson DH, Cunha BA. Life-threatening babesiosis inan asplenic patient treated with exchange transfusion, azithromycin,and atovaquone. Heart Lung 1998; 27:424–8.

399. Wittner M, Lederman J, Tanowitz HB, Rosenbaum GS, Weiss LM.Atovaquone in the treatment of Babesia microti infections in hamsters.Am J Trop Med Hyg 1996; 55:219–22.

400. Weiss LM, Wittner M, Tanowitz HB. The treatment of babesiosis. NEngl J Med 2001; 344:773.

401. Raoult D, Soulayrol L, Toga B, Dumon H, Casanova P. Babesiosis,pentamidine, and cotrimoxazole. Ann Intern Med 1987; 107:944.

402. Shaio MF, Yang KD. Response of babesiosis to a combined regimenof quinine and azithromycin. Trans R Soc Trop Med Hyg 1997; 91:214–5.

403. Shih CM, Wang CC. Ability of azithromycin in combination withquinine for the elimination of babesial infection in humans. Am JTrop Med Hyg 1998; 59:509–12.

404. Jacoby GA, Hunt JV, Kosinski K, et al. Treatment for transfusion-transmitted babesiosis by exchange transfusion. N Engl J Med1980; 303:1098–100.

405. Powell VI, Grima K. Exchange transfusion for malaria and Babesiainfection. Transfus Med Rev 2002; 16:239–50.

Documents

The Clinical Assessment, Treatment, and Prevention of Lyme ......IDSA Guidelines • CID 2006:43 (1 November) • 1091 Figure 1. From left to right, an Ixodes scapularis larva, nymph,